Cycloalkane Derivatives

ABSTRACT

Disclosed herein are therapeutic agents and/or preventive agents for pain or therapeutic agents and/or preventive agents for a sodium channel associated disease. The present invention provides compounds represented by the following formula (I) or pharmacologically acceptable salts thereof:

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel cycloalkane derivative, apharmacologically acceptable salt, or a hydrate thereof, useful as apharmaceutical, particularly, with an analgesic action. The presentinvention further relates to a method for treating and/or preventingpain by administering the novel cycloalkane derivative of the presentinvention. The present invention also relates to the compound, apharmacologically acceptable salt, or a hydrate thereof, for treatingand/or preventing the crisis of a sodium channel associated disease. Inaddition, the present invention relates to a method for treating and/orpreventing a sodium channel associated disease by administering thenovel cycloalkane derivative of the present invention.

2. Description of the Related Art

A variety of pains including acute pain such as inflammatory pain andnociceptive pain; intractable chronic pain such as neurogenic pain,myogenic pain and fibromyalgia; and phantom limb pain probably derivedfrom a psychogenic factor are known as pathologic pains. Since paingreatly degrades the quality of life of a patient in many cases, socialloss caused by pain is incalculable.

Currently, nonsteroidal analgesics, nonnarcotic analgesics, narcoticanalgesics, antiepileptic drugs and antidepressants are used astherapeutic agents for pain. Although a method for treating most casesof inflammatory pain and nociceptive pain has been established, thereare very limited effective therapeutic agents for chronic pains such asneurogenic pain for which a nonsteroidal antiinflammatory drug isineffective and which is resistant to narcotic analgesics.

Pregabalin and the like are currently used as therapeutic agents forneurogenic pain, but it is reported that pregabalin shows an effectivetherapeutic ratio based on self-evaluation of patients of painfuldiabetic neuropathy of approximately 50% (Non Patent Literature 1), andhence, it cannot be said that patient satisfaction with treatment isalways attained.

Voltage-gated sodium channels (Nays) are ion channels each including anα subunit having four domains and auxiliary β subunits, at least ninesubtypes thereof have been reported so far, and these subtypesrespectively have different expression distributions and physiologicalactions so as to regulate biological functions.

The sodium channels are an essence of neural activity, and drugs such asa local anesthetic of lidocaine, an antiarrhythmic of mexiletine and anantiepileptic of carbamazepine are known as inhibitors of the sodiumchannels. Such drugs have, however, low selectivity for the Navsubtypes. Since sodium channels of different subtypes are expressed inmuscles, cardiac muscle cells and the central nervous system as shown inTable 1, there arises a problem of an adverse drug action caused whensuch a drug is systemically administered.

TABLE 1 Subtype Main expression site Nav1.1 Central nervous systemNav1.2 Central nervous system Nav1.3 Central nervous system Nav1.4Skeletal muscle Nav1.5 Cardiac muscle cells Nav1.6 Sensory/motor nervoussystem Nav1.7 Sensory nervous system Nav1.8 Sensory nervous systemNav1.9 Sensory nervous system

On the other hand, it is known that Nav 1.7 defect causes paininsensitivity in a human (Non Patent Literature 2), and since similartendency is observed in KO mice (Non Patent Literature 3), it isregarded that a Nav 1.7 selective inhibitor is a promising target oftherapeutic agents for various pains.

Patent Literature 1 relates to a Nav 1.7 modulator and specificallydescribes, for example, a compound represented by formula (A) below (inExample 811). The feature of the compound described in this patentliterature is that two aromatic rings are connected through an oxygenatom, and further, N-substituted sulfonamide is connected to one of thearomatic rings (phenyl group). The compound of the present inventiondiffers therefrom in that cycloalkane is connected to an aromatic ringthrough an oxygen atom. Patent Literature 1 neither describes norsuggests the structure of the compound of the present invention.

Specifically, the compound disclosed in Patent Literature 1 is describedin the claim as falling within a structure represented by formula (B)below. The moiety B in this structure is defined as “phenyl or Het²,wherein Het² is defined as a 5- or 6-membered aromatic heterocyclicgroup containing (a) one to four nitrogen atoms, (b) one oxygen atom orone sulfur atom, or (c) one oxygen atom or one sulfur atom and one ortwo nitrogen atoms”. Thus, the moiety B is an aromatic substituent. Thepatent literature neither discloses that this moiety is a saturatedsubstituent nor discloses that cycloalkane is formed.

Patent Literature 2 relates to an N-type calcium channel inhibitor andspecifically describes, for example, a compound represented by formula(C) below (in Example 5(11)). The compound described in this patentliterature has a structure in which an aromatic ring and a saturatedheterocyclic ring are connected through a polymethylene(oxy) chain. AnN-substituted sulfonamide is bonded to aromatic ring (phenyl group), andtwo substituents are further introduced in the nitrogen atom of thissulfonamide. Specifically, the feature of this compound is that thenitrogen atom of the sulfonamide is di-substituted. The compound of thepresent invention differs therefrom in that: a saturated ring is not aheterocyclic ring; cycloalkane and an aromatic ring are connectedthrough an oxygen atom and not through a polymethylene chain; and asulfonamide moiety is mono-substituted at its nitrogen atom. PatentLiterature 2 neither describes nor suggests the compound of the presentinvention at all.

Neither does the compound of the present invention fall within astructure represented by formula (D) below described in claims of thePatent Literature 2, nor the structure of the compound of the presentinvention is suggested from the description related to this structure.

PRIOR ART LITERATURE Patent Literature

-   [Patent Literature 1] WO2010/079443-   [Patent Literature 2] WO2006/038594

Non Patent Literature

-   [Non Patent Literature 1] Drugs 64 (24): 2813-2820, 2004-   [Non Patent Literature 2] Cox, J. J. et al., Nature, 2006, 444    (7121), 894-898-   [Non Patent Literature 3] Nassar, M. A. et al., Proc. Natl. Acad.    Sci., 2004, 101(34), 12706-12711

SUMMARY OF THE INVENTION The Problem to be Solved by the Invention

An object of the present invention is to provide a sodium channelinhibitor that has high selectivity with high pain inhibitory activitiesand is further directed to reduction in adverse drug action caused bysystemic administration, in response to, for example, a low level ofsatisfaction at conventional therapeutic agents for neurogenic pain andthe low activities and selectivity of conventional sodium channelinhibitory activity.

The Means to Solve the Problem

The present inventors have earnestly conducted studies and consequentlycompleted the present invention by finding that a compound representedby formula (I) below having a structure in which a phenyl group to whichan N-aromatic substituent-substituted sulfonamide group is connected,and a cyclic alkyl group having an aromatic group as a substituent isconnected through an oxygen atom to the para position of the sulfonamidegroup, a salt, or a hydrate thereof, exhibits excellent pain control andsodium channel inhibitory activities with high selectivity.

Specifically, the present invention relates to:

(1) A compound represented by formula (I) or a pharmacologicallyacceptable salt, or hydrate thereof:

wherein Ar¹ and Ar² each independently represents a heteroaryl group oran aryl group,

R¹, R² and R³ each independently represents a hydrogen atom, a halogenatom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyC1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkylgroup or a cyano group,

R⁴ and R⁵ each independently represents a hydrogen atom, a halogen atom,a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl group,a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7cycloalkyl group or a C1-C6 alkoxy group, and

n represents an integer of 1 to 3, and

wherein the heteroaryl group or the aryl group optionally has one or twosubstituents independently selected from a halogen atom, a C1-C6 alkylgroup, a halogenated C1-C6 alkyl group, a hydroxyl group, a hydroxyC1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkylgroup, a carboxy group, a cyano group, an amino group, a C1-C3alkylamino group and a di-C1-C3 alkylamino group, and when theheteroaryl group or the aryl group has two substituents, the twosubstituents may be the same or different from each other.

The present invention further relates to the following:

(2) The compound or a pharmacologically acceptable salt thereofaccording to (1), wherein in formula (I), Ar¹ and Ar² each independentlyrepresents a heteroaryl group,

R¹, R² and R³ each independently represents a hydrogen atom, a halogenatom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group or a C3-C7cycloalkyl group, R⁴ and R⁵ each independently represents a hydrogenatom, a halogen atom, a C1-C6 alkyl group or a halogenated C1-C6 alkylgroup, and

the substituent on the heteroaryl group is one or two substituentsselected from the group consisting of a halogen atom, a C1-C6 alkylgroup, a halogenated C1-C6 alkyl group, a hydroxyl group, a hydroxyC1-C6 alkyl group, a C3-C7 cycloalkyl group, an amino group, a C1-C3alkylamino group and a di-C1-C3 alkylamino group.

(3) The compound or a pharmacologically acceptable salt thereofaccording to (1) or (2), wherein the heteroaryl group is a 5- or6-membered nitrogen-containing aromatic heterocyclic group.

(4) The compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (3), wherein Ar¹ is a pyridyl group, apyridazinyl group, a pyrimidinyl group, a pyrazolyl group or animidazolyl group optionally having a substituent.

(5) The compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (4), wherein Ar¹ is a pyridyl group, apyridazinyl group, a pyrimidinyl group, a pyrazolyl group or animidazolyl group optionally having one or two substituents selected fromthe group consisting of a chlorine atom, a fluorine atom, a methylgroup, an ethyl group, a trifluoromethyl group, an amino group, amethylamino group and a dimethylamino group.

(6) The compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (5), wherein Ar² is a thiadiazolyl group, athiazolyl group, a pyrimidinyl group, an isoxazolyl group, an oxazolylgroup or an isothiazolyl group optionally having a substituent.

(7) The compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (6), wherein Ar² is a thiadiazolyl group, athiazolyl group, a pyrimidinyl group, an isoxazolyl group, an oxazolylgroup or an isothiazolyl group optionally having a chlorine atom, afluorine atom or a methyl group as a substituent.

(8) The compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (7), wherein R¹, R² and R³ each independentlyrepresents a hydrogen atom, a chlorine atom, a fluorine atom, a methylgroup, an ethyl group, a trifluoromethyl group or a cyano group.

(9) The compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (8), wherein R⁴ and R⁵ each independentlyrepresents a hydrogen atom, a fluoro group or a methyl group.

(10) The compound, pharmacologically acceptable salt, or hydrate thereofaccording to (1), wherein the compound represented by formula (I) is

-   2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide;-   3-chloro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,5-difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,5-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-2-(3-amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-2-(3-amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-2-(3-amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,6-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide;    or-   2,6-difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide.

(11) The compound, pharmacologically acceptable salt, or hydrate thereofaccording to (1), wherein the compound represented by formula (I) is

-   2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,5-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,6-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;    or-   2,6-difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide.

(12) The compound or pharmacologically acceptable salt thereof accordingto (1), wherein the compound represented by formula (I) is

-   2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2,6-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;-   5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;-   4-{[(1S,2R)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;    or-   2,6-difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide.

(13) A pharmaceutical composition comprising a compound, apharmacologically acceptable salt, or a hydrate thereof according to anyof (1) to (12), and a pharmaceutically acceptable carrier.

(14) The pharmaceutical composition according to (13), for treatingand/or preventing pain.

(15) The pharmaceutical composition according to (13), for treatingand/or preventing a disease or symptom selected from the groupconsisting of acute pain; chronic pain; pain caused by injury of softtissues or peripheral tissues; postherpetic neuralgia; central pain;neuropathic pain; migraine; pain associated with osteoarthritis orrheumatoid arthritis; contusion; pain associated with sprain or trauma;spondylalgia; pain caused by injury of the spinal cord or brain stem;low back pain; sciatic neuralgia; toothache; myofascial pain syndrome;perineal section pain; gout pain; cardiac pain; muscle pain; eye pain;inflammatory pain; orofacial pain; abdominal pain; dysmenorrhea; laborpain or pain associated with endometriosis; somatic pain; painassociated with nerve or radicular injury; amputation; tic douloureux;pain associated with neuroma or vasculitis; pain caused by diabeticneuropathy or diabetic peripheral neuropathic pain; pain caused bychemotherapy-induced neuropathy; atypical prosopalgia; neuropathic lowback pain; trigeminal neuralgia; occipital neuralgia; myelomere orintercostal neuralgia; HIV-associated neuralgia; AIDS-associatedneuralgia; hyperalgesia; pain of thermal burn; idiopathic pain; paincaused by chemotherapy; occipital neuralgia; psychogenic pain; painassociated with gallstone; neuropathic or non-neuropathic painassociated with cancer; phantom limb pain; functional abdominal pain;headache; acute or chronic tension headache; sinus headache; clusterheadache; temporomandibular joint pain; maxillary sinus pain; paincaused by ankylosing spondylarthritis; postoperative pain; scar pain;chronic non-neuropathic pain; fibromyalgia; amyotrophic lateralsclerosis; epilepsy (particularly, partial epilepsy, adult epilepsypartial seizure and partial seizure of an epileptic patient); andgeneralized anxiety disorder and restless legs syndrome.

(16) The pharmaceutical composition according to (13), for treatingand/or preventing pain caused by diabetic neuropathy.

(17) The pharmaceutical composition according to (13), for treatingand/or preventing a sodium channel associated disease.

(18) Use of a compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (12), for producing a pharmaceuticalcomposition.

(19) The use according to (18), wherein the pharmaceutical compositionis a pharmaceutical composition for treating and/or preventing pain.

(20) The use according to (18), wherein the pharmaceutical compositionis a pharmaceutical composition for treating and/or preventing paincaused by diabetic neuropathy.

(21) The use according to (18), wherein the pharmaceutical compositionis a pharmaceutical composition for treating and/or preventing a sodiumchannel associated disease.

(22) A formulation intended for administration to a mammal for treatingand/or preventing pain, comprising a pharmacologically effective dose ofa compound or a pharmacologically acceptable salt thereof according toany of (1) to (12).

(23) The formulation according to (22), wherein the pain is pain causedby diabetic neuropathy.

(24) The formulation according to (23), wherein the mammal is a human.

(25) A sodium channel inhibitor comprising a pharmacologically effectivedose of a compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (12).

(26) The sodium channel inhibitor according to (25), wherein the sodiumchannel inhibitor is intended for administration to a mammal.

(27) The sodium channel inhibitor according to (26), wherein the mammalis a human.

(28) A method for treating and/or preventing pain, comprisingadministering a compound or a pharmacologically acceptable salt thereofaccording to any of (1) to (12).

(29) A method for treating and/or preventing a disease or symptomselected from the following group, comprising administering a compoundor a pharmacologically acceptable salt thereof according to any of (1)to (12): acute pain; chronic pain; pain caused by injury of soft tissuesor peripheral tissues; postherpetic neuralgia; central nervous pain;neuropathic pain; migraine; pain associated with osteoarthritis orrheumatoid arthritis; contusion; pain associated with sprain or trauma;spondylalgia; pain caused by injury of the spinal cord or brain stem;low back pain; sciatic neuralgia; toothache; myofascial pain syndrome;perineal section pain; gout pain; cardiac pain; muscle pain; eye pain;inflammatory pain; orofacial pain; abdominal pain; dysmenorrhea; laborpain or pain associated with endometriosis; somatic pain; painassociated with nerve or radicular injury; amputation; tic douloureux;pain associated with neuroma or vasculitis; pain caused by diabeticneuropathy or diabetic peripheral neuropathic pain; pain caused bychemotherapy-induced neuropathy; atypical prosopalgia; neuropathic lowback pain; trigeminal neuralgia; occipital neuralgia; myelomere orintercostal neuralgia; HIV-associated neuralgia; AIDS-associatedneuralgia; idiopathic pain; pain of thermal burn; pang; pain caused bychemotherapy; occipital neuralgia; psychogenic pain; pain associatedwith gallstone; neuropathic or non-neuropathic pain associated withcancer; phantom limb pain; functional abdominal pain; headache; acute orchronic tension headache; sinus headache; cluster headache;temporomandibular joint pain; maxillary sinus pain; pain caused byankylosing spondylarthritis; postoperative pain; scar pain; chronicnon-neuropathic patient pain; fibromyalgia; amyotrophic lateralsclerosis; epilepsy (particularly, partial epilepsy, adult epilepsypartial seizure and partial seizure of an epileptic patient); andgeneralized anxiety disorder and restless legs syndrome.

(30) A method for treating and/or preventing pain caused by diabeticneuropathy, comprising administering a compound or a pharmacologicallyacceptable salt thereof according to any of (1) to (12).

(31) A method for treating and/or preventing a sodium channel associateddisease, comprising administering a compound or a pharmacologicallyacceptable salt thereof according to any of (1) to (12).

Advantageous Effects of Invention

The present compound represented by formula (I), a pharmacologicallyacceptable salt thereof, or a hydrate thereof has excellentvoltage-gated sodium channel 1.7 (Nav 1.7) inhibiting activities and hasexcellent subtype selectivity, and hence has an excellent pain reliefeffect and shows excellent sodium channel inhibiting activities inwarm-blooded animals (preferably mammals including humans).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing the powder x-ray diffraction of4-{[(1R,2S)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamidein a free form;

FIG. 2 is a diagram showing the powder x-ray diffraction of4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamidein a free form;

FIG. 3 is a diagram showing the powder x-ray diffraction of colorlesscrystals 1 of5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamidein a free form;

FIG. 4 is a diagram showing the powder x-ray diffraction of colorlesscrystals 2 of5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamidein a free form; and

FIG. 5 is a diagram showing the powder x-ray diffraction of2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamidein a free form.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described in detail.

In the present specification, a “halogen atom” refers to a fluorineatom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, a “C1-C6 alkyl group” refers to a linearor branched alkyl group having 1 to 6 carbon atoms, and includes amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a 2-methylbutyl group, a neopentylgroup, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutylgroup, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a1,3-dimethylbutyl group, a 2,3-dimethylbutyl group and a 2-ethylbutylgroup.

In the present specification, a “C1-C3 alkyl group” refers to a linearor branched alkyl group having 1 to 3 carbon atoms, and includes, forexample, a methyl group, an ethyl group, a propyl group and an isopropylgroup.

In the present specification, a “halogenated C1-C6 alkyl group” refersto a group obtained by substituting a “C1-C6 alkyl group” defined abovewith a “halogen atom” defined above. The number of halogen atoms assubstituents is not particularly limited but the substitution may befrom mono-substitution to per-substitution. The substitution position isnot particularly limited but the terminal carbon atom of the alkyl groupis more preferably mono-substituted. The halogenated C1-C6 alkyl groupincludes, for example, a trifluoromethyl group, a trichloromethyl group,a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, afluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethylgroup, a 2-bromoethyl group, a 2-chloroethyl group, a 2-fluoroethylgroup, a 2-iodoethyl group, a 3-chloropropyl group, a 4-fluorobutylgroup and a 6-iodohexyl group.

In the present specification, a “hydroxy C1-C6 alkyl group” refers to agroup obtained by substituting a “C1-C6 alkyl group” defined above witha hydroxy group. The substitution position of the hydroxy group is notparticularly limited but the terminal carbon atom of the alkyl group ismore preferably substituted. The hydroxy C1-C6 alkyl group includes, forexample, a hydroxymethyl group, a 2-hydroxyethyl group, a3-hydroxypropyl group, a 4-hydroxybutyl group, a 5-hydroxypentyl group,a 6-hydroxyhexyl group, a 1-hydroxyethyl group, a 1-hydroxypropyl groupand a 2-hydroxypropyl group.

In the present specification, a “C1-C6 alkoxy group” refers to a groupformed by bonding an oxygen atom to the terminal of a “C1-C6 alkylgroup” defined above. The C1-C6 alkoxy group includes, for example, amethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxygroup, a pentoxy group, an isopentoxy group, a 2-methylbutoxy group, aneopentoxy group, a hexyloxy group, a 4-methylpentoxy group, a3-methylpentoxy group and a 2-methylpentoxy group.

In the present specification, a “C1-C6 alkoxy C1-C6 alkyl group” refersto a group obtained by substituting a “C1-C6 alkyl group” defined abovewith a “C1-C6 alkoxy group” defined above. The substitution position ofthe alkoxy group is not particularly limited but the terminal carbonatom of the alkyl group is preferably substituted. The C1-C6 alkoxyC1-C6 alkyl group includes, for example, a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a butoxymethyl group, a3-methoxypropyl group, a 3-ethoxypropyl group, a 4-methoxybutyl group, a5-methoxypentyl group and a 6-methoxyhexyl group.

In the present specification, a “C3-C7 cycloalkyl group” refers to asaturated cyclic hydrocarbon group having 3 to 7 carbon atoms, andincludes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group and a cycloheptyl group.

In the present specification, a “C1-C3 alkylamino group” refers to anamino group which one “C1-C3 alkyl group” defined above is bonded to itsnitrogen atom. The C1-C3 alkylamino group includes, for example, amethylamino group, an ethylamino group, a propylamino group and anisopropylamino group.

In the present specification, a “di-C1-C3 alkylamino group” refers to anamino group which two “C1-C3 alkyl groups” defined above are bonded toits nitrogen atom. The two alkyl groups may be the same or differentfrom each other. The di-C1-C3 alkylamino group includes, for example, adimethylamino group, an ethylmethylamino group, a diethylamino group, amethylpropylamino group, an ethylpropylamino group, a dipropylaminogroup, an isopropylmethylamino group, an ethylisopropylamino group and adiisopropylamino group.

In the present specification, an “aryl group” refers to an aromatichydrocarbon substituent and includes, for example, a phenyl group and anaphthyl group, and the aryl group may be bonded in any position.

In the present specification, a “heteroaryl group” refers to a 5- or6-membered aromatic heterocyclic substituent having 1 to 4 heteroatomsindependently selected from the group consisting of a nitrogen atom, anoxygen atom and a sulfur atom. The heteroaryl group includes, forexample, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, apyrazinyl group, a triazolyl group, a pyrazolyl group, an imidazolylgroup, a tetrazolyl group, an isoxazolyl group, an oxazolyl group, anisothiazolyl group, a thiazolyl group, a thiadiazolyl group, anoxadiazolyl group, a thiophenyl group and a furanyl group. Such anaromatic heterocyclic group may be bonded in any position (it is notedthat the above-described names of the groups are mentioned merely asgeneric designation of substituents but do not specify bondingposition).

The compound of the present invention has a structure represented byformula (I). Specifically, an N-monoaromatic substituent-substitutedsulfonamide group is bonded to a phenyl group (the aromatic group on thenitrogen atom of this sulfonamide group is referred to as Ar²); acycloalkyl group is connected through an oxygen atom to the paraposition with respect to the position at which the sulfonamide group isbonded; and an aromatic group (referred to as Ar¹) is bonded to thecarbon atom adjacent to the carbon atom where the cycloalkyl group isbonded to the oxygen atom.

In the compound of formula (I), two aromatic groups represented by Ar¹and Ar² may each independently represent an aryl group (aromatichydrocarbon group) or a heteroaryl group (aromatic heterocyclic group).Each of these aromatic groups may further have a substituent. Also, thephenyl group to which a sulfonamide is connected may have from one tothree substituents. The cycloalkyl group connected through the oxygenatom to the phenyl group to which sulfonamide is connected can be any 5-to 7-membered ring in size. This ring may have 1 or 2 substituents, andwhen the ring has two such groups, the two groups may be the same ordifferent from each other.

The aromatic group Ar¹ may be an aryl group but more preferably is aheteroaryl group. The heteroaryl group can be any monocyclic 5- or6-membered ring containing 1 to 4 heteroatoms. The heteroatom(s) arepreferably nitrogen atom(s).

The 5-membered heteroaryl group can be selected from those exemplifiedabove but is preferably a group containing only nitrogen atom(s) asheteroatom(s). Preferable examples thereof can include a pyrazolyl groupand an imidazolyl group. A pyrazolyl group is more preferred.

The connecting position of such a 5-membered heteroaryl group to thecyclic alkyl group is not particularly limited. In the case of apyrazolyl group or an imidazolyl group, examples can includepyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl andimidazol-4-yl. Among them, pyrazol-3-yl, pyrazol-4-yl, imidazol-4-yl orthe like is preferred.

The 6-membered heteroaryl group preferably contains only nitrogenatom(s) as heteroatom(s), as in the 5-membered ring. A pyridyl group ora pyridazinyl group is preferred. The binding site is not limited but ispreferably pyridin-4-yl, pyridin-3-yl or pyridazin-4-yl.

Ar¹ may have a substituent and may have 1 or 2 substituentsindependently selected from the group consisting of a halogen atom, aC1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, ahydroxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, an amino group, aC1-C3 alkylamino group and a di-C1-C3 alkylamino group. Among them, ahalogen atom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, anamino group, a C1-C3 alkylamino group or a di-C1-C3 alkylamino group ismore preferred. Examples of such substituents can include a chlorineatom, a fluorine atom, a methyl group, an ethyl group, a trifluoromethylgroup, an amino group, a methylamino group and a dimethylamino group.The substituent of Ar¹ is preferably an amino group or an alkyl group.The alkyl group is preferably a methyl group or an ethyl group. Thealkyl group may substitute on a nitrogen atom or a carbon atom.

Examples of Ar¹ can include a phenyl group, a 1H-pyrazol-4-yl group, a1-methyl-1H-pyrazol-5-yl group, a 1-ethyl-1H-pyrazol-5-yl group, a3-amino-1H-pyrazol-4-yl group, a 1H-imidazol-1-yl group, a1-methyl-1H-imidazol-5-yl group, a pyridin-3-yl group, a2-aminopyridin-3-yl group, a 2-methylpyridin-3-yl group and a2-pyridazin-4-yl group. Among them, a phenyl group, a1-methyl-1H-pyrazol-5-yl group, a 1-ethyl-1H-pyrazol-5-yl group, a1H-pyrazol-4-yl group or a 3-amino-1H-pyrazol-4-yl group is preferred.

Likewise, the aromatic group Ar² is more preferably a heteroaryl group.The heteroaryl group can be any 5- or 6-membered ring containing two ormore heteroatoms. Examples of the 5-membered heteroaryl group caninclude an imidazolyl group, a triazolyl group, an isoxazolyl group, anoxazolyl group, an isothiazolyl group, a thiazolyl group, a thiadiazolylgroup and an oxadiazolyl group. Examples of the 6-membered heteroarylgroup can include a pyridyl group, a pyrimidinyl group, a pyridazinylgroup and a pyrazinyl group. Among them, a thiadiazolyl group, athiazolyl group or a pyrimidinyl group is more preferred.

Ar² may have a substituent and may have 1 or 2 substituentsindependently selected from the group consisting of a halogen atom, aC1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, ahydroxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, an amino group, aC1-C3 alkylamino group and a di-C1-C3 alkylamino group. Among them, ahalogen atom or a C1-C6 alkyl group is preferred. Such a substituent isa chlorine atom, a fluorine atom or a methyl group.

Examples of Ar² can include a 1,2,4-thiadiazol-5-yl group, a1,3-thiazol-4-yl group, a pyrimidin-4-yl group, a 6-fluoropyrimidin-4-ylgroup and a 2-fluoropyrimidin-4-yl group. Among them, a pyrimidin-4-ylgroup is more preferred.

The phenyl group constituting the benzenesulfonamide may have from 1 to3 substituents. Examples of such substituents can include a halogenatom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyC1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkylgroup and a cyano group. Among them, a halogen atom, a C1-C6 alkyl groupor a halogenated C1-C6 alkyl group is preferred. One to three groupsindependently selected from a chlorine atom, a fluorine atom, a methylgroup, an ethyl group, a trifluoromethyl group and a cyano group aremore preferred. When the phenyl group has two or more such groups, thetwo or more groups may be the same or different from each other.

Examples of the optionally substituted phenyl group constituting thebenzenesulfonamide can include a 3-methylphenyl group, a 3-chlorophenylgroup, a 3-fluorophenyl group, a 2,3-difluorophenyl group, a2,5-difluorophenyl group, a 2,6-difluorophenyl group, a2-chloro-5-fluorophenyl group, a 5-chloro-2-fluorophenyl group, a3-trifluoromethylphenyl group, a 2-fluoro-3-methylphenyl group, a2-fluoro-5-methylphenyl group, a 5-ethyl-2-fluorophenyl group, a3-cyanophenyl group and a 5-cyano-2-fluorophenyl group. Among them, a2-fluorophenyl group, a 2,5-difluorophenyl group, a5-chloro-2-fluorophenyl group or a 2-fluoro-3-methylphenyl group ispreferred (here, the position number is indicated with the positionbonded to the sulfonamide group as 1).

The cycloalkyl moiety can be any 5- to 7-membered cyclic alkyl but ispreferably 5- or 6-membered cyclic alkyl.

This cycloalkyl group may have 1 or 2 substituents independentlyselected from the group consisting of a halogen atom, a C1-C6 alkylgroup, a halogenated C1-C6 alkyl group, a hydroxyl group, a hydroxyC1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkylgroup and a C1-C6 alkoxy group. Among them, a halogen atom, a C1-C6alkyl group or a halogenated C1-C6 alkyl group is preferred. A fluorineatom or a methyl group is more preferred.

In the compound of the present invention, the aromatic group Ar¹ on thecycloalkyl group and the phenyloxy moiety having the sulfonamide groupcan be substituted on adjacent carbon atoms to form the following fourisomers having diastereomeric relationship, all of which are included inthe present invention. Among them, the more preferred conformation isthat of (1b).

The present compound represented by formula (I) may be in the form of apharmacologically acceptable salt if desired. A pharmacologicallyacceptable salt means a salt that is not greatly toxic but may be usedas a pharmaceutical. The present compound represented by formula (I) maybe changed into the form of a salt by causing a reaction between thecompound and an acid if it has a basic group.

Examples of salts based on a basic substituent and a basic heteroarylgroup include halogenated hydroacid salts such as hydrofluoride,hydrochloride, hydrobromide and hydroiodide; inorganic acid salts suchas hydrochloride, nitrate, perchlorate, sulfate and phosphate; loweralkane sulfonates such as methanesulfonate, trifluoromethanesulfonateand ethanesulfonate; aryl sulfonates such as benzenesulfonate andp-toluenesulfonate; organic acid salts such as acetate, malate,fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate;and amino acid salts such as glycine salt, lysine salt, arginine salt,ornithine salt, glutamate and aspartate. Among these, preferably,inorganic acid salts or aryl sulfonate is used, and more preferably,hydrochloride, benzenesulfonate or p-toluenesulfonate is used.

Examples of salts based on an acidic substituent include alkali metalsalts such as sodium salt, potassium salt and lithium salt; alkali earthmetal salts such as calcium salt and magnesium salt; metal salts such asaluminum salt and iron salt; inorganic salts such as ammonium salt;amine salts of organic salts such as t-octyl amine salt, dibenzylaminesalt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt,ethylenediamine salt, N-methylglucamine salt, guanidine salt,diethylamine salt, triethylamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt,diethanolamine salt, N-benzylphenethylamine salt, piperazine salt,tetramethylammonium salt, tris(hydroxymethyl)aminomethane salt; andamino acid salts such as glycine salt, lysine salt, arginine salt,ornithine salt, glutamate and aspartate.

When the compound represented by formula (I) is allowed to stand in theair or recrystallized, it may absorb moisture to have absorbed water, soas to be changed into a hydrate, and such a hydrate is also included inthe salt of the present invention.

The compound represented by formula (I) or a salt thereof sometimesabsorbs a solvent of a given type so as to be changed into a solvate,and such a solvate is also included in the salt of the presentinvention.

The compound represented by formula (I) has asymmetric carbon atoms inits molecule and thus includes optical isomers. These isomers andmixtures of these isomers are all represented by a single formula, i.e.,formula (I). Accordingly, single optical isomers of the compoundrepresented by formula (I) and mixtures of these optical isomers at anyratio are all included in the scope of the present invention.

The optical isomers as described above can be obtained by synthesizingthe compound according to the present invention by using opticallyactive starting compounds or using the approach of asymmetric synthesisor asymmetric induction. Alternatively, the optical isomers can beobtained by isolation from the synthesized compound according to thepresent invention by using a general optical resolution method or, forexample, a separation method using an optically active carrier.

The present compounds may also contain, at a non-natural ratio, atomicisotope(s) of one or more of the atoms constituting such a compound.Examples of the atomic isotope(s) include deuterium (²H), tritium (³H),iodine-125 (¹²⁵I) and carbon-14 (¹⁴C). Moreover, the compounds may beradiolabeled with a radioisotope such as tritium (³H), iodine-125 (¹²⁵I)or carbon-14 (¹⁴C) Such a radiolabeled compound is useful as therapeuticor preventive agents, research reagents, for example, assay reagents,and diagnostic agents, for example, in vivo image diagnostic agents. Allisotopic variants of the present compounds are included in the scope ofthe present invention no matter whether or not they are radioactive.

The present compound represented by formula (I) and a pharmacologicallyacceptable salt thereof have excellent voltage-gated sodium channel 1.7(Nav 1.7) inhibiting activities and have excellent subtype selectivity,and hence have an excellent pain relief effect as well as showingexcellent sodium channel inhibiting activities in warm-blooded animals(preferably mammals including humans).

Accordingly, the present compound and a pharmacologically acceptablesalt thereof have excellent treatment efficacy and/or preventiveefficacy for the following diseases or symptoms: Pain caused by diabeticneuropathy; acute pain; chronic pain; pain caused by injury of softtissues or peripheral tissues; postherpetic nerve pain; central pain;neuropathic pain; megrim; pain associated with osteoarthritis orrheumatoid arthritis; contusion; pain associated with sprain or injury;spondylalgia; pain caused by damage of the spinal cord or brain stem;low back pain; sciatic neuralgia; toothache; myofascial pain syndrome;perineal section pain; gout pain; cardiac pain; muscle pain; eye pain;inflammatory pain; orofacial pain; abdominal pain; dysmenorrhea; laborpain or pain associated with endometriosis; somatic pain; painassociated with nerve or radicular injury; amputation; tic douloureux;pain associated with neuroma or vasculitis; pain caused by diabeticneuropathy or diabetic peripheral neuropathic pain; pain caused bychemotherapy-induced neuropathy; atypical prosopalgia; neuropathic lowback pain; trigeminal neuralgia; occipital neuralgia; myelomere orintercostal neuralgia; HIV-associated neuralgia; AIDS-associatedneuralgia; hyperalgesia; pain of thermal burn; idiopathic pain; paincaused by chemotherapy; occipital neuralgia; psychogenic pain; painassociated with gallstone; neuropathic or non-neuropathic painassociated with cancer; phantom limb pain; functional abdominal pain;headache; acute or chronic tension headache; sinus headache; clusterheadache; temporomandibular joint pain; maxillary sinus pain; paincaused by ankylosing spondylitis; postoperative pain; scar pain; chronicnon-neuropathic pain, fibromyalgia and the like.

The present compound can be expected to further show excellent treatmentefficacy and/or preventive efficacy for dysuria, multiple sclerosis,interstitial cystitis, cystalgia syndrome, irritable colon syndrome,dysuric multiple sclerosis, irregular pulse, myotonia, numbness, braininfarction and the like.

The present compound or a pharmacologically acceptable salt thereof canbe administered in various forms. Examples of the route ofadministration include oral administration using tablets, capsules,granules, emulsions, pills, powders, syrups (solutions) and the like,and parenteral administration using injections (intravenous,intramuscular, subcutaneous or intraperitoneal administration), dripinfusions, suppositories (rectal administration) and the like. Thesevarious formulations can be prepared as drug products according tousually employed methods by appropriately selecting and using aidsgenerally used in the field of pharmaceutical formulation, such asexcipients, binders, disintegrants, lubricants, flavoring agents,dissolving aids, suspending agents and coating agents, to be added to anactive ingredient.

When used as a tablet, examples of a usable carrier include excipientssuch as lactose, saccharose, sodium chloride, glucose, urea, starch,calcium carbonate, kaolin, crystalline cellulose and silicic acid;binders such as water, ethanol, propanol, simple syrup, a glucosesolution, a starch solution, a gelatin solution, carboxymethylcellulose,shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone;disintegrants such as dry starch, sodium alginate, powdered agar,powdered laminaran, sodium hydrogencarbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate,stearic monoglyceride, starch and lactose; disintegration inhibitorssuch as saccharose, stearin, cocoa butter and hydrogenated oil;absorption enhancers such as quaternary ammonium salt and sodium laurylsulfate; humectants such as glycerine and starch; adsorbents such asstarch, lactose, kaolin, bentonite and colloidal silicic acid; andlubricants such as purified talc, stearate, powdered boric acid andpolyethylene glycol. Furthermore, tablets having a general coating, forexample, sugar-coated tablets, gelatin-coated tablets, enteric-coatedtablets, film-coated tablets, double-layer tablets and multilayeredtablets can be prepared as required.

When used as a pill, examples of a usable carrier include excipientssuch as glucose, lactose, cocoa butter, starch, hydrogenated vegetableoil, kaolin and talc; binders such as powdered gum arabic, powderedtragacanth, gelatin and ethanol; and disintegrants such as laminaran andagar.

When used as a suppository, a wide range of carriers conventionallyknown in this field can be used, and examples include polyethyleneglycol, cocoa butter, higher alcohols, higher alcohol esters, gelatinand semisynthetic glycerides.

When used as an injection, the formulations can be prepared as asolution, an emulsion or a suspension. These solutions, emulsions andsuspensions are preferably sterilized and isotonic with blood. A solventused for producing these solutions, emulsions and suspensions is notparticularly limited so long as it can be used as a diluent for medicaluse, and examples of the solvent include water, ethanol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcoholand polyoxy ethylene sorbitan fatty acid esters. In this case, asufficient amount of sodium chloride, glucose or glycerine may beincluded in the formulation to prepare an isotonic solution, and generaldissolving aids, buffers, soothing agents and the like may also beincluded.

Furthermore, coloring agents, preservatives, perfumes, flavoring agents,sweeteners and the like can be added to the above-mentioned formulationsif necessary. Moreover, other pharmaceuticals can also be added.

The amount of active ingredient compound contained in the formulationsis not particularly limited but is widely and appropriately selected,and is generally 0.5 to 70% by weight and preferably 1 to 30% by weightof the whole composition.

The dose varies depending on the symptoms, age and the like of a patient(a warm-blooded animal, in particular, a human). In the case of oraladministration, a daily dosage for an adult is from a lower limit of 0.1mg (preferably 1 mg and more preferably 10 mg) to an upper limit of 2000mg (preferably 100 mg), which is administered dividedly as 1 to 6 dosesdepending upon the symptoms.

The present compound represented by formula (I) can be produced inaccording with methods A to C described below. The compound representedby formula (V) can be produced in according with methods D to H.

Solvents used in reactions of respective steps of the methods A to Kbelow are not particularly limited as long as they do not inhibit thereactions but dissolve to some extent compounds involved in thereactions. The solvents are selected from, for example, the groupconsisting of the following solvents. Alternatively, the solvents may bemixtures thereof. The group of usable solvents consists of hydrocarbonssuch as pentane, hexane, octane, petroleum ether, ligroin andcyclohexane; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-Pyrrolidinoneand hexamethylphosphoric triamide; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethylene glycol dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, 2-butanol, 2-methyl-1-propanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,cyclohexanol and methyl cellosolve; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile,propionitrile, butyronitrile and isobutyronitrile; esters such as ethylformate, ethyl acetate, propyl acetate, butyl acetate and diethylcarbonate; ketones such as acetone, methyl ethyl ketone,4-methyl-2-pentanone, methyl isobutyl ketone, isophorone andcyclohexanone; nitro compounds such as nitro ethane and nitro benzene;halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane,chlorobenzene, dichlorobenzene, chloroform and carbon tetrachloride;aromatic hydrocarbons such as benzene, toluene and xylene; carboxylicacids such as acetic acid, formic acid, propionic acid, butyric acid andtrifluoroacetic acid; and water.

Examples of bases used in the reactions described below include alkalimetal carbonates such as sodium carbonate, potassium carbonate, lithiumcarbonate and cesium carbonate; alkali metal hydrogencarbonates such assodium hydrogencarbonate, potassium hydrogencarbonate and lithiumhydrogencarbonate; alkali metal hydrides such as lithium hydride, sodiumhydride and potassium hydride; alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide;inorganic bases of alkali metal fluorides such as sodium fluoride andpotassium fluoride; alkali metal alkoxides such as sodium methoxide,sodium ethoxide, sodium-t-butoxide, potassium methoxide, potassiumethoxide, potassium-t-butoxide and lithium methoxide; alkali metaltrialkyl siloxides such as sodium trimethylsiloxide, potassiumtrimethylsiloxide and lithium trimethylsiloxide; mercaptan alkali metalssuch as methyl mercaptan sodium and ethyl mercaptan sodium; organicbases such as N-methyl morpholine, triethylamine, tripropylamine,tributylamine, diisopropylethylamine, dicyclohexylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,quinoline, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU); andorganometallic bases such as butyl lithium, lithium diisopropylamide andlithium bis(trimethylsilyl)amide.

Examples of acids used in the reactions described below include:inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid,perchloric acid, hypochlorous acid, phosphoric acid, boric acid,hydrofluoric acid, tetrafluoroboric acid and fluorosulfonic acid;organic acids such as formic acid, acetic acid, oxalic acid, citricacid, gluconic acid, lactic acid, tartaric acid, benzoic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andtrifluoromethanesulfonic acid; and Lewis acids such as borontrifluoride, a boron trifluoride-diethyl ether complex, a borontrifluoride-dimethyl sulfide complex, a boron trifluoride-pyridinecomplex, a boron trifluoride-tetrahydrofuran complex, boron trichloride,boron triiodide, trimethylaluminum, triethylaluminum and titaniumtetrachloride.

Examples of palladium catalysts used in the reactions described belowinclude divalent or zero-valent palladium catalysts such astetrakis(triphenylphosphine) palladium (0), palladium-activated carbon,palladium hydroxide-activated carbon, palladium (II) acetate, palladium(II) trifluoroacetate, palladium black, palladium (II) bromide,palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide,palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate,dichlorobis(acetonitrile) palladium (II), dichlorobis(benzonitrile)palladium (II), dichloro(1,5-cyclooctadiene) palladium (II),acetylacetone palladium (II), palladium (II) sulfide,[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,[1,2-bis(diphenylphosphino)ethane]palladium (II), dichloridetris(dibenzylidene-acetone)dipalladium (0), tetrakis(acetonitrile)palladium (II) tetrafluoroborate and an aryl chloride-palladium dimer.

Examples of copper catalysts used in the reactions described belowinclude zero-valent, monovalent or divalent copper catalysts andcomplexes thereof, such as copper, copper (I) chloride, copper (I)bromide, copper (I) iodide, copper (I) trifluoromethanesulfonate, acopper (I) bromide-dimethyl sulfide complex, copper (II) bromide, copper(II) acetate, copper (II) sulfate and copper (II) acetate.

Examples of a ligand of the copper catalyst used in the reactionsdescribed below include diamine ligands, such asN,N′-dimethylethylenediamine,trans-N,N′-dimethylcyclohexane-1,2-diamine,2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl,1,10-phenanthroline and N,N′-dimethyl-1,2-cyclohexanediamine.

Examples of dehydrogenation or halogen metal exchange reagents used inthe reactions described below include: alkyl alkali metals such asmethyl lithium, ethyl lithium, isopropyl lithium, n-butyl lithium,sec-butyl lithium and tert-butyl lithium; alkyl magnesium halides suchas methyl magnesium chloride, methyl magnesium bromide, ethyl magnesiumchloride, ethyl magnesium bromide, isopropyl magnesium chloride andisopropyl magnesium bromide; and organic metal bases such as lithiumdiisopropylamide, lithium tetramethylpiperidine and lithiumbis(trimethylsilyl)amide.

Examples of hydroboration reagents used in the reactions described belowinclude: borane complexes such as a borane-tetrahydrofuran complex, aborane-dimethyl sulfide complex, a borane-dimethylamine complex and aborane-morpholine complex; and dialkyl borane such asisopinocampheylborane, disiamylborane and 9-borabicyclo[3.3.1]nonane.

Examples of oxidation reagents used in the reactions described belowinclude hydrogen peroxide water and sodium perborate tetrahydrate.

Examples of an epoxidation reagent used in the reaction of step F1described below include: peracids such as 3-chloroperbenzoic acid,perbenzoic acid and peracetic acid; peroxides such as t-butylhydroperoxide (TBHP) and hydrogen peroxide; and potassiumperoxymonosulfate.

Examples of reducing agents used in the reactions described belowinclude: alkali metal borohydrides such as sodium borohydride, lithiumborohydride, sodium cyanoborohydride and sodium triacetoxyborohydride;borane complexes such as a borane-tetrahydrofuran complex and aborane-dimethyl sulfide complex; aluminum hydride compounds such asdiisobutyl aluminum hydride, lithium aluminum hydride and lithiumtriethoxyaluminium hydride; and alkali metals such as sodium telluriumhydride, diisobutyl aluminum hydride and sodium bis(methoxyethoxy)aluminum hydride.

In the reaction conducted in each step of the methods A to I, thereaction temperature is varied depending upon the solvent, startingmaterial, reagent and the like, and the reaction time is varieddepending upon the solvent, starting material, reagent, reactiontemperature and the like.

In the reaction conducted in each step of the methods A to I, aftercompleting the reaction, an objective compound is collected from areaction mixture according to a method generally employed in thistechnical field. For example, the reaction mixture is appropriatelyneutralized, and if there is an insoluble material, it is removed byfiltration. Thereafter, water and a water-nonmiscible organic solventsuch as ethyl acetate are added to the resultant, so as to separate anorganic layer containing the objective compound. The organic layer iswashed with water or the like, dried over anhydrous magnesium sulfate,anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate or thelike, and filtered, and the solvent is evaporated, so as to yield theobjective compound.

The thus obtained objective compound may be, if necessary, separated andpurified by a method generally employed in this technical field, forexample, by appropriate combination of methods usually employed forseparation/purification of an organic compound, such asrecrystallization and reprecipitation, followed by elution with anappropriate eluent by using chromatography. If the objective compound isinsoluble in a solvent, it may be purified by washing a solid crudeproduct with that solvent. Alternatively, the objective compound of eachstep may be used as it is in a next reaction without purification.

Next, reactions conducted in respective steps of the methods A to K willbe described.

The method. A is a method for producing the compound represented byformula (I).

[Method A]

In the present specification, Ar¹, Ar², R¹, R², R³, R⁴, R⁵ and nrepresent the same as defined above, P, P¹, P², P³ and P⁴ eachrepresents a protecting group, X represents a halogen atom, Y representsa substituent that can work as a nucleophile or an electrophile in across-coupling reaction caused by a transition-metal catalyst, such as ahalogen atom, a substituent including a boron atom, or a substituentincluding a tin atom.

P, P¹ or P² is not particularly limited as long as it is a protectinggroup generally used for an amino group. Examples thereof include aformyl group, a phenylcarbonyl group, a methoxycarbonyl group, anethoxycarbonyl group, a t-butoxycarbonyl group, a phenyloxycarbonylgroup, a 9-fluorenylmethyloxycarbonyl group, an adamantyloxycarbonylgroup, a benzyloxycarbonyl group, a benzylcarbonyl group, a benzylgroup, a 2,4-dimethoxybenzyl group, a benzhydryl group, a trityl groupand a phthaloyl group.

P³ or P⁴ is not particularly limited as long as it is acetal generallyused as a protecting group for a carbonyl group. The protecting groupis, for example, a methyl group or an ethyl group. P³ or P⁴ may have acyclic structure forming a 1,3-dioxane or 1,3-dioxolane ring.

Y is not particularly limited as long as it is used as a substituentthat can work as a nucleophile or an electrophile in a cross-couplingreaction caused by a transition-metal catalyst. Examples thereof includean iodo group, a bromo group, a chloro group, a boronyl group and atributylstannyl group.

Step A1

This step is the step of producing a compound represented by formula(IV).

This step is conducted by causing a reaction, in a solvent and in thepresence of a base, between a compound represented by formula (II) and acompound represented by formula (III).

The compound represented by formula (II) and the compound represented byformula (III) used in this step are known compounds or may be easilyproduced from known compounds used as starting materials by knownmethods or methods similar to the known methods.

The solvent used in this step is preferably any one of ethers, nitrilesor halogenated hydrocarbons, and more preferably, tetrahydrofuran,acetonitrile or dichloromethane.

The base used in this step is preferably any one of alkali metalcarbonates or organic bases, and more preferably, potassium carbonate,pyridine, 4-(N,N-dimethylamino)pyridine, 1,4-diazabicyclo[2.2.2]octane(DABCO), LiHMDS or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The reaction temperature to be employed in this step is generally 0° C.to 100° C. and preferably 0° C. to room temperature.

The reaction time of this reaction is from 0.5 hours to 48 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 24 hours.

Step A2

This step is the step of producing a compound represented by formula(VI).

This step is conducted by causing a reaction, in a solvent and in thepresence of a base, between the compound represented by formula (IV) anda compound represented by formula (V).

The solvent used in this step is preferably any one of ethers or amides,and more preferably, tetrahydrofuran or N,N-dimethylformamide.

The base used in this step is preferably any one of alkali metalalkoxides, alkali metal hydrides or alkali metal hydroxides, and morepreferably, sodium t-butoxide, potassium t-butoxide, sodium methoxide,potassium methoxide, sodium hydride, potassium hydride, sodium hydroxideor potassium hydroxide.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably 0° C. to room temperature.

The reaction time of this reaction is from 0.5 hours to 48 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 24 hours.

Step A3

This step is the step of producing the compound represented by formula(I).

This step is conducted by causing a reaction, in a solvent and, ifdesired, in the presence of a scavenger, between an acid and thecompound represented by formula (VI).

The solvent used in this step is preferably any one of ethers orhalogenated hydrocarbons, and more preferably, tetrahydrofuran,1,4-dioxane or dichloromethane.

The scavenger used in this step is preferably trialkylsilane or arylether, and more preferably, triethylsilane or anisole.

The acid used in this step is preferably an organic acid or an inorganicacid, and more preferably, trichloroacetic acid, trifluoroacetic acid,acetic acid, sulfuric acid or hydrochloric acid.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 150° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

Also, this step is conducted by deprotecting the compound represented byformula (VI) in a solvent and in the presence of a palladium catalystunder the hydrogen atmosphere.

The solvent used in this case is preferably any one of ethers oralcohols, and more preferably, tetrahydrofuran, methanol or ethanol.

The catalyst is preferably a zero-valent palladium catalyst, and morepreferably, palladium-activated carbon or palladium hydroxide-activatedcarbon.

The reaction temperature is generally −20° C. to 120° C. and preferably0° C. to 80° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

A compound represented by formula (Ia) or (Ib) is an optical isomer ofthe compound represented by formula (I) and is produced by combining themethod A with method B described below.

The method B is a method for producing optical isomers (VIa) and (VIb)of the compound (VI) by optical resolution after step A2 in the methodA. The compound represented by formula (Ia) or (Ib) is produced throughstep A3 from the optical isomer (VIa) or (VIb).

[Method B]

In the above formulas, Ar¹, Ar², R¹, R², R³, R⁴, R⁵, P and n representthe same as defined above.

Step B1

This step is the step of producing the compounds represented by formulas(VIa) and (VIb). This step is conducted by an optical resolution of thecompound represented by formula (VI) into the compounds represented by(VIa) and (VIb) by using a chiral column.

The solvent used in this step is preferably any one of hydrocarbons,alcohols or mixed solvents thereof, and more preferably, a mixed solventof hexane and isopropanol or a mixed solvent of hexane and ethanol.

The column used in the optical resolution is not particularly limited aslong as it is a chiral column capable of optical resolution. CHIRALPAK(registered trademark) AD-H or CHIRALPAK (registered trademark) ICmanufactured by Daicel Corp. is preferred.

The temperature to be employed in this step is generally 0° C. to 40° C.and preferably 0° C. to room temperature. The method C is another methodfor producing the compound represented by formula (I).

[Method C]

In the above formulas, Ar¹, Ar², R¹, R², R³, R⁴, R⁵, P², X and nrepresent the same as defined above.

Step C1

This step is the step of producing a compound represented by formula(VIII).

This step is conducted by causing a reaction, in a solvent and in thepresence of a base, between a compound represented by formula (II) and acompound represented by formula (VII).

The compound represented by formula (II) and the compound represented byformula (VII) used in this step are known compounds or may be easilyproduced from known compounds used as starting materials by knownmethods or methods similar to the known methods.

The solvent used in this step is preferably any one of ethers, nitrilesor halogenated hydrocarbons, and more preferably, tetrahydrofuran,acetonitrile or dichloromethane.

The base used in this step is preferably any one of alkali metalcarbonates or organic bases, and more preferably, potassium carbonate,pyridine, 4-(N,N-dimethylamino)pyridine, 1,4-diazabicyclo[2.2.2]octane(DABCO), LiHMDS or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The reaction temperature to be employed in this step is generally 0° C.to 100° C. and preferably 0° C. to room temperature.

The reaction time of this reaction is from 0.5 hours to 48 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 24 hours.

Step C2

This step is the step of producing a compound represented by formula(IX).

This step is conducted by causing a reaction, in a solvent and in thepresence of a base, between the compound represented by formula (V) andthe compound represented by formula (VIII).

The solvent used in this step is preferably any one of ethers or amides,and more preferably, tetrahydrofuran or N,N-dimethylformamide.

The base used in this step is preferably any one of alkali metalalkoxides, alkali metal hydrides or alkali metal hydroxides, and morepreferably, sodium t-butoxide, potassium t-butoxide, sodium methoxide,potassium methoxide, sodium hydride, potassium hydride, sodium hydroxideor potassium hydroxide.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably 0° C. to room temperature.

The reaction time of this reaction is from 0.5 hours to 48 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 24 hours.

Step C3

This step is the step of producing a compound represented by formula(X).

This step is conducted by causing a reaction, in a solvent and, ifdesired, in the presence of a scavenger, between an acid and thecompound represented by formula (IX).

The solvent used in this step is preferably any one of ethers orhalogenated hydrocarbons, and more preferably, tetrahydrofuran,1,4-dioxane or dichloromethane.

The scavenger used in this step is preferably trialkylsilane or arylether, and more preferably, triethylsilane or anisole.

The acid used in this step is preferably an organic acid or an inorganicacid, and more preferably, trichloroacetic acid, trifluoroacetic acid,acetic acid, sulfuric acid or hydrochloric acid.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 150° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

Alternatively, this step is also conducted by deprotecting the compoundrepresented by formula (IX) in a solvent and in the presence of apalladium catalyst under the hydrogen atmosphere.

The solvent used in this case is preferably any one of ethers oralcohols, and more preferably, tetrahydrofuran, methanol or ethanol.

The catalyst used is preferably a zero-valent palladium catalyst, andmore preferably, palladium-activated carbon or palladiumhydroxide-activated carbon.

The reaction temperature is generally −20° C. to 120° C. and preferably0° C. to 80° C.

The reaction time is generally 1 hour to 48 hours and preferably 2 hoursto 24 hours.

Step C4

This step is the step of producing the compound represented by formula(I).

This step is conducted by causing a reaction, in a solvent and in thepresence of a base, between the compound represented by formula (X) anda compound represented by formula (XI). This step may be conducted inthe presence of a copper catalyst and a ligand thereof.

The compound represented by formula (XI) used in this step is a knowncompound or may be easily produced from known compounds used as startingmaterials by known methods or methods similar to the known methods.

The solvent used in this step is preferably any one of ethers, amides orhalogenated hydrocarbons, and more preferably, tetrahydrofuran,N,N-dimethylformamide or dichloromethane.

The base used in this step is preferably any one of organic bases oralkali metal carbonates, and more preferably, triethylamine, cesiumcarbonate or potassium carbonate.

The copper catalyst used in this step is preferably copper (I) chloride,copper (I) bromide, copper (I) iodide or copper (I)trifluoromethanesulfonate.

The ligand used in this step is preferably N,N′-dimethylethylenediamine,trans-N,N′-dimethylcyclohexane-1,2-diamine orN,N′-dimethyl-1,2-cyclohexanediamine.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 150° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

The compound represented by formula (V) can be produced in accordingwith methods D to H.

The method D is a method for producing the compound represented byformula (V).

[Method D]

In the above formulas, Ar¹, R⁴, R⁵ and n represent the same as definedabove.

Step D1

This step is the step of producing the compound represented by formula(V).

This step is conducted by converting a compound represented by formula(XIII) to a metal salt by deprotonation or halogen metal exchange in asolvent and then reacting the metal salt with a compound represented byformula (XII).

The compound represented by formula (XII) and the compound representedby formula (XIII) used in this step are known compounds or may be easilyproduced from known compounds used as starting materials by knownmethods or methods similar to the known methods.

The solvent used in this step is preferably any one of ethers,hydrocarbons or halogenated hydrocarbons, and more preferably,tetrahydrofuran, toluene or dichloromethane.

The deprotonation or halogen metal exchange reagent used in this step ispreferably alkyl magnesium halide or alkyl alkali metal, and morepreferably, n-butyl lithium, sec-butyl lithium or isopropyl magnesiumchloride.

The reaction temperature to be employed in this step is generally −100°C. to 100° C. and preferably −80° C. to room temperature.

The reaction time of this reaction is from 0.5 hours to 48 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 24 hours.

The method E is another method for producing the compound represented byformula (V).

[Method E]

In the above formulas, Ar¹, R⁴, R⁵, Y and n represent the same asdefined above.

Step E1

This step is the step of producing a compound represented by formula(XVI).

This step is conducted by causing a reaction, in a solvent and in thepresence of a catalyst, between a compound represented by formula (XIV)and a compound represented by formula (XV).

The compounds represented by formulas (XIV) and (XV) used in this stepare known compounds or may be easily produced from known compounds usedas starting materials by known methods or methods similar to the knownmethods.

The solvent used in this step is preferably any one of ethers, amides,water or mixed solvents thereof, and more preferably, a mixed solvent of1,4-dioxane or water, tetrahydrofuran or N,N-dimethylformamide.

The catalyst used in this step is preferably a zero-valent palladiumcatalyst or a divalent palladium catalyst, and more preferably,tetrakis(triphenylphosphine)palladium (0),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride or[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride.

The reaction temperature to be employed in this step is generally 0° C.to 150° C. and preferably room temperature to 120° C.

The reaction time of this reaction is from 0.5 hours to 60 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 48 hours.

Step E2

This step is the step of producing the compound represented by formula(V).

This step is conducted by hydroborating the compound represented byformula (XVI) in a solvent, followed by oxidation.

The solvent used in this step is preferably any one of ethers, and morepreferably, 1,4-dioxane or tetrahydrofuran.

The hydroboration agent used in this step is preferably aborane-tetrahydrofuran complex or a borane-dimethyl sulfide complex.

The oxidizing agent used in this step is preferably hydrogen peroxide orsodium perborate tetrahydrate.

The reaction temperature to be employed in this step is generally 0° C.to 150° C. and preferably room temperature to 120° C.

The reaction time of this reaction is from 0.5 hours to 60 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 48 hours.

The method F is another method for producing the compound represented byformula (V).

[Method F]

In the above formulas, Ar¹, R⁴, R⁵ and n represent the same as definedabove.

Step F1

This step is the step of producing a compound represented by formula(XVII).

This step is conducted by epoxidizing the compound represented byformula (XVI) in a solvent.

The solvent used in this step is preferably any one of ketones orhalogenated hydrocarbons, and more preferably, chloroform ordichloromethane.

The epoxidation reagent used in this step is preferably3-chloroperbenzoic acid or potassium peroxymonosulfate.

The reaction temperature to be employed in this step is generally −20°C. to 120° C. and preferably 0° C. to 80° C.

The reaction time of this step is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

Step F2

This step is the step of producing the compound represented by formula(V).

This step is conducted by reducing the compound represented by formula(XVII) in a solvent.

The solvent used in this step is preferably any one of ethers oralcohols, and more preferably, tetrahydrofuran, methanol or ethanol.

The reducing agent used in this step is preferably any one of alkalimetal borohydrides or aluminum hydride compounds, and more preferably,sodium borohydride or lithium aluminum hydride.

The reaction temperature to be employed in this step is generally −20°C. to 120° C. and preferably 0° C. to 80° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

This step is also conducted by reducing the compound represented byformula (XVII) in a solvent and in the presence of a catalyst under ahydrogen atmosphere or under a nitrogen atmosphere in the presence of acatalyst.

The solvent used in this step is preferably any one of ethers oralcohols, and more preferably, tetrahydrofuran, methanol or ethanol.

The catalyst used in this step is preferably a palladium catalyst or anickel catalyst, and more preferably, palladium-activated carbon,palladium hydroxide-activated carbon or Raney nickel.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 120° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

The method G is another method for producing the compound represented byformula (V).

[Method G]

In the above formulas, Ar¹, R⁴, R⁵, P¹, P², Y and n represent the sameas defined above.

Step G1

This step is the step of producing a compound represented by formula(XIX).

This step is conducted by causing a reaction, in a solvent and in thepresence of a catalyst, between a compound represented by formula(XVIII) and a compound represented by formula (XV).

The compounds represented by formulas (XVIII) and (XV) used in this stepare known compounds or may be easily produced from known compounds usedas starting materials by known methods or methods similar to the knownmethods.

The solvent used in this step is preferably any one of ethers, amides,water or mixed solvents thereof, and more preferably, a mixed solvent of1,4-dioxane and water, tetrahydrofuran or N,N-dimethylformamide.

The catalyst used in this step is preferably a zero-valent palladiumcatalyst or a divalent palladium catalyst, and more preferably,tetrakis(triphenylphosphine)palladium (0),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride or[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride.

The reaction temperature to be employed in this step is generally 0° C.to 150° C. and preferably room temperature to 120° C.

The reaction time of this reaction is from 0.5 hours to 60 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 48 hours.

Step G2

This step is the step of producing the compound represented by formula(V).

This step is conducted by reducing the compound represented by formula(XIX) in a solvent.

The solvent used in this step is preferably any one of ethers oralcohols, and more preferably, tetrahydrofuran, ethanol or methanol.

The reducing agent used in this step is preferably any one of alkalimetal borohydrides or aluminum hydride compounds, and more preferably,sodium borohydride or lithium aluminum hydride.

The reaction temperature to be employed in this step is generally −20°C. to 120° C. and preferably 0° C. to 80° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

This step is also conducted by reducing the compound represented byformula (XIX) in a solvent and in the presence of a catalyst under ahydrogen atmosphere or under a nitrogen atmosphere in the presence of acatalyst.

The solvent used in this step is preferably any one of ethers oralcohols, and more preferably, tetrahydrofuran, methanol or ethanol.

The catalyst used in this step is preferably a palladium catalyst or anickel catalyst, and more preferably, palladium-activated carbon,palladium hydroxide-activated carbon or Raney nickel.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 120° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

A compound represented by formula (Va) or (Vb) is an optical isomer ofthe compound represented by formula (V) and is produced by combining themethods D to G with method H described below.

The method H is a method for producing the optical isomers (Va) and (Vb)of the compound (V) by optical resolution. The compound represented byformula (Ia) or (Ib) is produced through steps A2 and A3 from theoptical isomer (Va) or (Vb).

[Method H]

In the above formulas, Ar¹, R⁴, R⁵ and n represent the same as definedabove.

Step H1

This step is the step of producing the compounds represented by formulas(Va) and (Vb). This step is conducted by optically resolving thecompound represented by formula (V) into the compounds represented byformulas (Va) and (Vb) by using a chiral column.

The solvent used in this step is preferably any one of hydrocarbons,alcohols or mixed solvents thereof, and more preferably, a mixed solventof hexane and isopropanol or a mixed solvent of hexane and ethanol.

The column used in the optical resolution can be any of thoseexemplified above.

The temperature to be employed in this step is generally 0° C. to 40° C.and preferably 0° C. to room temperature.

The method I is another method for producing the compound represented byformula (XVI).

In the above formulas, Ar¹, R⁴, R⁵ and n represent the same as definedabove.

Step I1

This step is the step of producing a compound represented by formula(XXI).

This step is conducted by converting a compound represented by formula(XIII) to a metal salt by deprotonation or halogen metal exchange in asolvent and then reacting the metal salt with a compound represented byformula (XX).

The compounds represented by formulas (XIII) and (XX) used in this stepare known compounds or may be easily produced from known compounds usedas starting materials by known methods or methods similar to the knownmethods.

The solvent used in this step is preferably any one of ethers,hydrocarbons or halogenated hydrocarbons, and more preferably,tetrahydrofuran, toluene or dichloromethane.

The deprotonation or halogen metal exchange reagent used in this step ispreferably alkyl magnesium halide or alkyl alkali metal, and morepreferably, n-butyl lithium, sec-butyl lithium or isopropyl magnesiumchloride.

The reaction temperature to be employed in this step is generally −100°C. to 100° C. and preferably −80° C. to room temperature.

The reaction time of this reaction is from 0.5 hours to 48 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 24 hours.

Step 12

This step is the step of producing the compound represented by formula(XVI).

This step is conducted by causing a reaction, in a solvent, between anacid and the compound represented by formula (XXI).

The solvent used in this step is preferably any one of alcohols,aromatic hydrocarbons or halogenated hydrocarbons, and more preferably,ethanol, toluene or dichloromethane.

The acid used in this step is preferably an organic acid or an inorganicacid, and more preferably, hydrochloric acid, sulfuric acid, acetic acidor p-toluenesulfonic acid.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 150° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

[Method J]

In the above formulas, Ar¹, R⁴, R⁵, P³, P⁴, Y and n represent the sameas defined above.

Step J1

This step is the step of producing a compound represented by formula(XXII).

This step is conducted by causing a reaction, in a solvent and in thepresence of a dehydrating agent or under dehydration conditions, betweenan acid and the compound represented by formula (XVIII).

The solvent used in this step is preferably any one of aromatichydrocarbons, and more preferably, toluene or benzene.

The acid used in this step is preferably an organic acid or an inorganicacid, and more preferably, hydrochloric acid, sulfuric acid orp-toluenesulfonic acid.

The dehydrating agent used in this step is preferably orthoester, andmore preferably, hydrochloric acid or trimethoxymethane,trimethoxyethane or triethoxyethane.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 150° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

Step J2

This step is the step of producing a compound represented by formula(XXIII).

This step is conducted by causing a reaction, in a solvent and in thepresence of a catalyst, between the compound represented by formula(XXII) and a compound represented by formula (XV).

The compound represented by formula (XV) used in this step is a knowncompound or may be easily produced from known compounds used as startingmaterials by known methods or methods similar to the known methods.

The solvent used in this step is preferably any one of ethers, amides,water or mixed solvents thereof, and more preferably, a mixed solvent of1,4-dioxane and water, tetrahydrofuran or N,N-dimethylformamide.

The catalyst used in this step is preferably a zero-valent palladiumcatalyst or a divalent palladium catalyst, and more preferably,tetrakis(triphenylphosphine)palladium (0),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride or[1,2-bis(diphenylphosphino)ethane]palladium (II) dichloride.

The reaction temperature to be employed in this step is generally 0° C.to 150° C. and preferably room temperature to 120° C.

The reaction time of this reaction is from 0.5 hours to 60 hours, andthe reaction is generally completed in approximately 1 hour toapproximately 48 hours.

Step J3

This step is the step of producing the compound represented by formula(XIX).

This step is conducted by causing a reaction, in an aqueous solvent,between an acid and the compound represented by formula (XXIII).

The solvent used in this step is preferably any one of alcohols orethers, and more preferably, ethanol, 1,4-dioxane or tetrahydrofuran.

The acid used in this step is preferably an organic acid or an inorganicacid, and more preferably, hydrochloric acid or sulfuric acid.

The reaction temperature to be employed in this step is generally 0° C.to 200° C. and preferably room temperature to 150° C.

The reaction time of this reaction is from 1 hour to 48 hours, and thereaction is generally completed in approximately 2 hours toapproximately 24 hours.

The method K is another method for producing an optically activecompound represented by formula (XVIIb) of the compound represented byformula (XVII). Also, an enantiomer thereof may be produced byappropriately selecting a reagent in step K1.

[Method K]

In the above formulas, Ar¹, R⁴, R⁵ and n represent the same as definedabove.

Step K1

This step is the step of producing a compound represented by formula(XXIV).

This step is conducted by converting the compound represented by formula(XVI) to optically active diol in a solvent.

The solvent used in this step is preferably any one of alcohols, wateror mixed solvents thereof, and more preferably, a mixed solvent oft-butanol and water.

The reagent for asymmetric conversion to diol used in this step ispreferably AD-mixα or AD-mixβ (Sigma-Aldrich Corp.).

The reaction temperature to be employed in this step is generally −20°C. to 120° C. and preferably 0° C. to 80° C.

The reaction time of this step is on the order of 1 hour to 48 hours,and the reaction is generally completed in approximately 2 hours toapproximately 24 hours.

Step K2

This step is the step of producing the compound represented by formula(XVIIb).

This step is conducted by subjecting the compound represented by formula(XXIV) to (I) a reaction with orthoester in the presence of an acid,(II) a reaction with acid halide in the presence of a base, or (III) atreatment with a base, in a solvent.

The solvent used in (I) is preferably any one of halogenatedhydrocarbons, and more preferably, dichloromethane.

The acid used in (I) is preferably an inorganic acid or an organic acid,and more preferably, hydrochloric acid, sulfuric acid orp-toluenesulfonic acid.

The orthoester used in (I) is preferably trimethoxymethane,trimethoxyethane or triethoxyethane.

The reaction temperature to be employed in (I) is generally −20° C. to120° C. and preferably 0° C. to 80° C.

The reaction time of (I) is from 1 hour to 96 hours, and the reaction isgenerally completed in approximately 2 hours to approximately 48 hours.

The solvent used in (II) is preferably any one of nitriles, and morepreferably, acetonitrile.

The base used in (II) is preferably any one of alkali metal salts, andmore preferably, potassium bromide, sodium bromide or lithium bromide.

The acid halide used in (II) is preferably acetic acid halide, formicacid halide or propionic acid halide, and more preferably, propionylbromide or acetyl bromide.

The reaction temperature to be employed in (II) is generally −20° C. to120° C. and preferably 0° C. to room temperature.

The reaction time of (II) is from 1 hour to 48 hours, and the reactionis generally completed in approximately 2 hours to approximately 24hours.

The solvent used in (III) is preferably any one of alcohols, and morepreferably, ethanol or methanol.

The base used in (III) is preferably any one of alkali metal carbonates,and more preferably, potassium carbonate, lithium carbonate or sodiumcarbonate.

The reaction temperature to be employed in (III) is generally −20° C. to120° C. and preferably 0° C. to room temperature.

The reaction time of (III) is from 1 hour to 48 hours, and the reactionis generally completed in approximately 2 hours to approximately 24hours.

EXAMPLES

The present invention will now be described in more detail withreference to examples and test examples, but the scope of the presentinvention is not limited to these examples.

In the examples described below, elution in column chromatography wasperformed under observation by TLC (Thin Layer Chromatography). In theTLC observation, silica gel 60F254 manufactured by Merck & Co. wasadopted as a TLC plate; a solvent used as an eluting solvent in columnchromatography was adopted as a developing solvent; and a UV detectorwas adopted as a detection method. Silica gel SK-85 (230-400 mesh) alsomanufactured by Merck & Co. or Chromatorex NH (200-350 mesh)manufactured by Fuji Silysia Chemical Ltd. was used as silica gel forcolumns. In addition to general column chromatography, an automaticchromatography apparatus (Purif-α2 or Purif-espoir2) manufactured byShoko Scientific Co., Ltd. was appropriately used. A solvent describedin each example was used as an eluting solvent at a specified ratio (orat a ratio changed appropriately if necessary). Abbreviations used inthe examples mean the following:

mg: milligram, g: gram, mL: milliliter, MHz: megahertz.

In the examples described below, nuclear magnetic resonance(hereinafter, referred to as ¹H-NMR) spectra were indicated in δ values(ppm) in terms of chemical shift values with tetramethylsilane used asstandard. Splitting patterns were represented by s for singlet, d fordoublet, t for triplet, q for quartet, m for multiplet, and br forbroad.

Powder x-ray diffraction data was determined with the followingequipment under the following measurement conditions:

Equipment manufacturer: Rigaku Corp.

Model: RINT TTR-III

Source: Cu-Kα rays

Wavelength (angstrom): 1.54

Detector: scintillation counter

Optical system: parallel beam method

Tube voltage (kV): 50

Tube current (mA): 300

Scanning range 2θ (deg): 2 to 40

Sampling step (deg): 0.02

Scanning rate (deg/min): 2

Sample holder: non-reflecting sample holder

Example 12,5-Difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(1a)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

To a solution ofN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 600 mg, 1.35 mmol) and (1S*,2R*)-2-phenylcyclohexanol(240 mg, 1.36 mmol) in DMSO (6.0 mL), sodium hydride (63%; 100 mg, 2.63mmol) was added with cooling on ice, and the reaction solution wasstirred at room temperature for 1 hour. Water (100 mL) was added to thereaction solution, followed by extraction with ethyl acetate (50 mL).The thus obtained organic layer was washed twice with water (200 mL) anddried over anhydrous sodium sulfate. After vacuum concentration, theresidue was purified with silica gel chromatography (hexane/ethylacetate=4:1) to yield the title compound (270 mg, 33%) as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-1.68 (4H, m), 1.86-2.05 (3H, m),2.17-2.21 (1H, m), 2.82-2.89 (1H, m), 3.65 (3H, s), 3.71 (3H, s), 4.25(1H, dt, d=3.9, 10.6 Hz), 5.21 (2H, s), 6.18 (1H, d, J=2.4 Hz),6.30-6.34 (2H, m), 7.13-7.24 (6H, m), 7.34 (1H, dd, J=6.7, 10.2 Hz),8.17 (1H, s).

(1b)2,5-Difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

To a solution of theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(270 mg, 0.449 mmol) prepared in Example 1a and triethylsilane (0.30 mL)in dichloromethane (3.0 mL), trifluoroacetic acid (3.0 mL) was added atroom temperature, and the reaction solution was stirred for 1 hour. Thereaction solution was concentrated, and the residue was purified withsilica gel chromatography (dichloromethane/methanol=95:5) to yield thetitle compound (186 mg, 92%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.39-1.70 (4H, m), 1.82-2.02 (3H, m),2.20-2.23 (1H, m), 2.83-2.89 (1H, m), 4.27 (1H, dt, d=4.33, 10.6 Hz),6.47 (1H, dd, J=5.1, 11.4 Hz), 7.10-7.21 (5H, m), 7.49 (1H, dd, J=4.7,9.8 Hz), 8.05 (1H, s).

MS (FAB) m/z: 452 [M+H]+.

Example 22,5-Difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(2a)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by usingN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 126 mg, 0.283 mmol), (1S,2R)-2-phenylcyclohexanol (50.0mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0mL), to yield the title compound (55.7 mg, 33%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-1.68 (4H, m), 1.86-2.05 (3H, m),2.17-2.21 (1H, m), 2.82-2.89 (1H, m), 3.65 (3H, s), 3.71 (3H, s), 4.25(1H, dt, d=3.9, 10.6 Hz), 5.21 (2H, s), 6.18 (1H, d, J=2.4 Hz),6.30-6.34 (2H, m), 7.13-7.24 (6H, m), 7.34 (1H, dd, J=6.7, 10.2 Hz),8.17 (1H, s).

(2b)2,5-Difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(55.7 mg, 0.0926 mmol) prepared in Example 2a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (31.0 mg, 74%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.39-1.70 (4H, m), 1.82-2.02 (3H, m),2.20-2.23 (1H, m), 2.83-2.89 (1H, m), 4.27 (1H, dt, d=4.33, 10.6 Hz),6.47 (1H, dd, J=5.1, 11.4 Hz), 7.10-7.21 (5H, m), 7.49 (1H, dd, J=4.7,9.8 Hz), 8.05 (1H, s).

MS (ESI) m/z: 452 [M+H]+;

[α]_(D) ²⁵=−53.24 (c 0.216, DMSO).

Example 32,5-Difluoro-4-{[(1R*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(3a)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1R*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 177 mg, 0.397 mmol), (1R*,2R*)-2-phenylcyclohexanol(70.0 mg, 0.397 mmol), sodium hydride (63%; 30.3 mg, 0.794 mol) and DMSO(5.0 mL), to yield the title compound (53.0 mg, 22%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.47-1.70 (4H, m), 1.78-1.81 (1H, m),1.95-1.99 (1H, m), 2.07-2.10 (1H, m), 2.28 (1H, dq, J=3.5, 12.9 Hz),2.87 (1H, dt, J=3.5, 11.7 Hz), 3.65 (3H, s), 3.72 (3H, s), 4.55 (1H, s),5.20 (1H, d, J=16.0 Hz), 5.25 (1H, d, J=16.0 Hz), 6.17 (1H, d, J=2.7Hz), 6.24 (1H, dd, J=2.7, 11.7 Hz), 6.33 (1H, dd, J=2.4, 8.6 Hz),7.13-7.28 (6H, m), 7.43 (1H, dd, J=6.3, 10.2 Hz), 8.16 (1H, s).

(3b)2,5-Difluoro-4-{[(1R*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(53.0 mg, 0.088 mmol) prepared in Example 3a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (44.6 mg, 99%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.50-1.80 (5H, m), 1.95-1.98 (1H, m),2.10-2.13 (1H, m), 2.29 (1H, dq, J=3.5, 12.5 Hz), 2.86 (1H, d, J=12.1Hz), 4.56 (1H, s), 6.39 (1H, dd, J=6.3, 11.3 Hz), 7.13-7.28 (5H, m),7.58 (1H, dd, J=6.7, 9.8 Hz), 8.04 (1H, s).

MS (ESI) m/z: 452 [M+H]+

Example 42,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(4a) (1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

To a solution of 1-methylpyrazole (9.34 g, 114 mmol) andN,N,N′,N′-tetramethylethylenediamine (17.1 mL, 114 mmol) in THF (300mL), butyl lithium (1.63 M solution in hexane; 81.7 mL, 133 mmol) wasadded at −78° C. The reaction solution was stirred at −78° C. for 30minutes. Then, cyclohexene oxide (13.9 mL, 137 mmol) was added thereto,and the mixture was stirred at room temperature for 15 hours. To thereaction solution, water (1 L) was added, followed by extraction withethyl acetate (500 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (ethyl acetate) to yield thetitle compound (11.2 g, 55%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.30-1.48 (4H, m), 1.76-1.91 (4H, m),2.09-2.15 (1H, m), 2.57-2.63 (1H, m), 3.59-3.65 (1H, m), 3.86 (3H, s),6.08 (1H, d, J=2.0 Hz), 7.44 (1H, d, J=2.0 Hz).

(4b)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 600 mg, 1.35 mmol),(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (240 mg, 1.33 mmol)prepared in Example 4a, sodium hydride (63%; 100 mg, 2.63 mmol) and DMSO(6.0 mL), to yield the title compound (340 mg, 42%) as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.39-1.70 (4H, m), 1.87-1.90 (1H, m),1.94-1.98 (1H, m), 2.05-2.09 (1H, m), 2.17-2.21 (1H, m), 2.97-3.03 (1H,m), 3.65 (3H, s), 3.74 (3H, s), 3.90 (3H, s), 4.08 (1H, dt, J=3.9, 10.2Hz), 5.21 (1H, d, J=15.7 Hz), 5.28 (1H, d, J=15.7 Hz), 6.04 (1H, d,J=2.0 Hz), 6.19 (1H, d, J=2.0 Hz), 6.34 (1H, dd, J=2.4, 8.6 Hz),6.34-6.39 (1H, m), 7.15 (1H, d, J=8.2 Hz), 7.36 (1H, d, J=1.6 Hz), 7.41(1H, dd, J=6.7, 10.2 Hz), 8.18 (1H, s).

(4c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(340 mg, 0.561 mmol) prepared in Example 4b, triethylsilane (0.4 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (259 mg, 43%) as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.37-1.60 (4H, m), 1.71-1.81 (2H, m),1.90-1.94 (1H, m), 2.16-2.19 (1H, m), 3.07-3.13 (1H, m), 3.79 (3H, s),4.57 (1H, dt, J=4.3, 9.8 Hz), 6.09 (1H, d, J=2.0 Hz), 7.22 (1H, d, J=2.0Hz), 7.34 (1H, dd, J=6.7, 11.7 Hz), 7.54 (1H, dd, J=6.7, 10.6 Hz), 8.53(1H, s).

MS (FAB) m/z: 456 [M+H]+.

Example 52,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamideNa salt

(5a) Tert-butyl[(2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using tert-butyl(1,3-thiazol-4-yl)[(2,4,5-trifluorophenyl)sulfonyl]carbamate (WO2010/079443; 219 mg, 0.555 mmol), the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (100 mg, 0.555 mmol)prepared in Example 4a, sodium hydride (63%; 42.3 mg, 1.11 mol) and DMF(3.0 mL), to yield the title compound (177 mg, 57%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.35 (9H, s), 1.44-1.70 (4H, m),1.88-1.91 (1H, m), 1.96-1.99 (1H, m), 2.06-2.10 (1H, m), 2.26-2.30 (1H,m), 3.00-3.06 (1H, m), 3.92 (3H, s), 4.18 (1H, dt, J=3.9, 10.2 Hz), 6.04(1H, d, J=2.0 Hz), 6.57 (1H, dd, J=6.3, 11.0 Hz), 7.36 (1H, d, J=2.0Hz), 7.49 (1H, d, J=2.4 Hz), 7.76 (1H, dd, J=6.3, 10.2 Hz), 8.78 (1H, d,J=2.4 Hz).

(5b)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the tert-butyl[(2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate(177 mg, 0.319 mmol) prepared in Example 5a, trifluoroacetic acid (1.0mL) and dichloromethane (1.0 mL), to yield the title compound (260 mg,87%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-1.69 (4H, m), 1.85-1.88 (1H, m),1.92-1.95 (1H, m), 2.03-2.07 (1H, m), 2.21-2.25 (1H, m), 2.95-3.01 (1H,m), 3.89 (3H, s), 4.09 (1H, dt, J=3.9, 10.6 Hz), 6.01 (1H, d, J=2.0 Hz),6.48 (1H, dd, J=6.3, 11.0 Hz), 6.89 (1H, d, J=2.4 Hz), 7.33 (1H, d,J=1.6 Hz), 7.51 (1H, dd, J=7.0, 10.2 Hz), 8.72 (1H, d, J=2.4 Hz).

(5c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamideNa salt

To a solution of the2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide(51.0 mg, 0.112 mmol) prepared in Example 5b in methanol (5.0 mL), a 1 Msodium hydroxide solution (0.112 mL, 0.112 mol) was added. The reactionsolution was concentrated to yield the title compound (47.0 mg, 88%) asa colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.24-2.01 (7H, m), 2.24-2.26 (1H, m),3.04-3.09 (1H, m), 3.86 (3H, s), 4.28-4.32 (1H, m), 6.14 (1H, s), 6.27(1H, s), 6.74-6.78 (1H, m), 7.27 (1H, s), 7.43-7.46 (1H, m), 8.53 (1H,s).

MS (ESI) m/z: 455 [M+H]+

Example 62,5-Difluoro-4-{[(1S*,2R*)-2-phenylcyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(6a)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 500 mg, 1.12 mmol), (1S*,2R*)-2-phenylcyclopentanol(200 mg, 1.23 mmol), sodium hydride (63%; 100 mg, 2.63 mol) and DMSO(5.0 mL), to yield the title compound (220 mg, 33%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.76-1.85 (1H, m), 1.92-1.98 (3H, m),2.14-2.21 (1H, m), 2.27-2.35 (1H, m), 3.30-3.35 (1H, m), 3.70 (6H, s),4.59-4.63 (1H, m), 5.27 (2H, s), 6.22 (1H, d, J=2.4 Hz), 6.32 (1H, dd,J=2.4, 8.2 Hz), 6.36-6.39 (1H, m), 7.15 (1H, d, J=8.6 Hz), 7.21-7.24(3H, m), 7.31-7.35 (2H, m), 7.48 (1H, dd, J=6.7, 10.2 Hz), 8.17 (1H, s).

(6b)2,5-Difluoro-4-{[(1S*,2R*)-2-phenylcyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(220 mg, 374 mmol) prepared in Example 6a, triethylsilane (0.3 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (155 mg, 95%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.75-1.83 (1H, m), 1.91-1.99 (3H, m),2.13-2.22 (1H, m), 2.26-2.34 (1H, m), 3.31-3.37 (1H, m), 4.63-4.66 (1H,m), 6.53 (1H, dd, J=6.3, 11.3 Hz), 7.21-7.23 (3H, m), 7.28-7.32 (2H, m),7.63 (1H, dd, J=7.0, 10.2 Hz), 8.07 (1H, s).

MS (ESI) m/z: 438 [M+H]+.

Example 72,5-Difluoro-4-{[(1S*,2R*)-2-phenylcycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(7a)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 350 mg, 0.786 mmol), (1S*,2R*)-2-phenylcycloheptanol(150 mg, 0.788 mmol), sodium hydride (63%; 60 mg, 1.58 mol) and DMSO(4.0 mL), to yield the title compound (140 mg, 29%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.49-1.68 (4H, m), 1.80-2.00 (6H, m),3.04 (1H, dt, J=2.4, 9.4 Hz), 3.62 (3H, s), 3.73 (3H, s), 4.37-4.41 (1H,m), 5.20 (1H, d, J=15.7 Hz), 5.25 (1H, d, J=15.7 Hz), 6.16 (1H, d, J=2.4Hz), 6.22 (1H, dd, J=6.3, 11.4 Hz), 6.33 (1H, dd, J=2.4, 8.2 Hz),7.13-7.25 (6H, m), 7.34 (1H, dd, J=6.7, 10.2 Hz), 8.16 (1H, s).

(7b)2,5-Difluoro-4-{[(1S*,2R*)-2-phenylcycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(140 mg, 0.227 mmol) prepared in Example 7a, triethylsilane (0.3 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (84.4 mg, 80%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.53-1.64 (4H, m), 1.81-2.01 (6H, m),3.05 (1H, dt, J=1.6, 9.8 Hz), 4.38-4.43 (1H, m), 6.35 (1H, dd, J=6.3,11.7 Hz), 7.10-7.24 (5H, m), 7.52 (1H, dd, J=6.7, 9.8 Hz), 8.04 (1H, s).

MS (ESI) m/z: 466 [M+H]+.

Example 82,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(8a) (1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)cyclopentanol

To a solution of 1-methylpyrazole (13.4 g, 163 mmol) in THF (1 L),n-butyl lithium (1.63 M solution in hexane; 100 mL, 163 mmol) was addeddropwise at −78° C. for 40 minutes. To the reaction solution,cyclopentene oxide (15.1 g, 179 mmol) was added at −78° C., and thereaction solution was stirred at room temperature for 20 hours. To thereaction solution, a saturated aqueous solution of sodiumhydrogencarbonate (100 mL) was added, followed by extraction with ethylacetate (500 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (dichloromethane/methanol=97:3)to yield the title compound (5.77 g, 21%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.63-1.91 (4H, m), 2.05-2.12 (1H, m),2.17-2.24 (1H, m), 3.03 (1H, q, J=8.3 Hz), 3.86 (3H, s), 4.24 (1H, q,J=6.4 Hz), 6.03 (1H, s), 7.39 (1H, s).

(8b)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by usingN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 500 mg, 1.12 mmol), the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (200 mg, 1.20 mmol)prepared in Example 8a, sodium hydride (63%; 100 mg, 2.63 mol) and DMSO(5.0 mL), to yield the title compound (340 mg, 51%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.76-1.99 (4H, m), 2.17-2.24 (1H, m),2.27-2.35 (1H, m), 3.44-3.50 (1H, m), 3.71 (6H, s), 3.87 (3H, s),4.57-4.61 (1H, m), 5.29 (2H, s), 6.06 (1H, d, J=2.0 Hz), 6.24 (1H, d,J=2.4 Hz), 6.34 (1H, dd, J=2.4, 8.2 Hz), 6.45 (1H, dd, J=6.3, 11.0 Hz),7.16 (1H, d, J=8.3 Hz), 8.41 (1H, d, J=2.0 Hz), 7.53 (1H, dd, J=6.7,10.2 Hz), 8.18 (1H, s).

(8c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(340 mg, 0.574 mmol) prepared in Example 8b, triethylsilane (0.4 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (211 mg, 83%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.76-2.00 (4H, m), 2.18-2.35 (2H, m),3.34-3.50 (1H, m), 3.87 (3H, s), 4.60-4.64 (1H, m), 6.07 (1H, d, J=1.6Hz), 6.59 (1H, dd, J=6.3, 11.0 Hz), 7.43 (1H, d, J=2.0 Hz), 7.66 (1H,dd, J=6.7, 9.8 Hz), 8.07 (1H, s).

MS (ESI) m/z: 442 [M+H]+.

Example 92,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(9a) (1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)cycloheptanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (3.66 g, 44.6 mmol),N,N,N′,N′-tetramethylethylenediamine (6.68 mL, 44.6 mmol), n-butyllithium (1.63 M solution in hexane; 32 mL, 52.2 mmol),1,2-epoxycycloheptane (5.0 g, 44.6 mmol) and THF (60 mL), to yield thetitle compound (1.13 g, 13%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.56-1.89 (9H, m), 1.98-2.05 (1H, m),2.76-2.82 (1H, m), 3.80-3.86 (1H, m), 3.84 (3H, s), 6.06 (1H, d, J=2.0Hz), 7.41 (1H, d, J=2.4 Hz).

(9b)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 450 mg, 1.01 mmol), the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (200 mg, 1.03 mmol)prepared in Example 9a, sodium hydride (63%; 100 mg, 2.63 mol) and DMSO(5.0 mL), to yield the title compound (146 mg, 23%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.58-1.97 (10H, m), 3.22 (1H, dt, J=2.7,9.4 Hz), 3.65 (3H, s), 3.74 (3H, s), 3.89 (3H, s), 4.30-4.35 (1H, m),5.23 (1H, d, J=16.0 Hz), 5.29 (1H, d, J=16.0 Hz), 6.01 (1H, d, J=2.0Hz), 6.19 (1H, d, J=2.4 Hz), 6.31-6.35 (2H, m), 7.16 (1H, d, J=8.6 Hz),7.35 (1H, d, J=1.6 Hz), 7.41 (1H, dd, J=6.7, 10.2 Hz), 8.18 (1H, s).

(9c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(146 mg, 0.236 mmol) prepared in Example 9b, triethylsilane (0.3 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (86.0 mg, 78%) as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.54-1.91 (10H, m), 3.26-3.29 (1H, m),3.77 (3H, s), 4.78-4.82 (1H, m), 6.12 (1H, s), 7.20 (1H, s), 7.28 (1H,dd, J=6.3, 11.7 Hz), 7.54 (1H, dd, J=6.7, 10.2 Hz), 8.52 (1H, s).

MS (ESI) m/z: 470 [M+H]+.

Example 105-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamideNa salt

(10a) Tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using thetert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid (WO 2010/079443; 479 mg, 1.17 mmol), the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (200 mg, 1.11 mmol)prepared in Example 4a, sodium hydride (63%; 84.5 mg, 2.22 mol) and DMF(10 mL), to yield the title compound (367 mg, 58%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.34 (9H, s), 1.40-1.67 (4H, m),1.86-1.89 (1H, m), 1.94-1.96 (1H, m), 2.05-2.08 (1H, m), 2.21-2.25 (1H,m), 3.02-3.09 (1H, m), 3.93 (3H, s), 4.21 (1H, dt, J=3.9, 10.2 Hz), 6.03(1H, d, J=2.0 Hz), 6.55 (1H, d, J=11.7 Hz), 7.34 (1H, d, J=1.6 Hz), 7.48(1H, d, J=2.0 Hz), 8.00 (1H, d, J=7.4 Hz), 8.77 (1H, d, J=2.4 Hz).

(10b)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using thetert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid (367 mg, 0.643 mmol) prepared in Example 10a, trifluoroacetic acid(1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (304mg, 99%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.38-1.69 (4H, m), 1.85-1.89 (1H, m),1.92-1.95 (1H, m), 2.05-2.07 (1H, m), 2.18-2.21 (1H, m), 3.00-3.06 (1H,m), 3.92 (3H, s), 4.10-4.16 (1H, m), 6.02 (1H, d, J=2.0 Hz), 6.48 (1H,d, J=11.7 Hz), 6.89 (1H, d, J=2.4 Hz), 7.34 (1H, d, J=2.0 Hz), 7.80 (1H,d, J=2.4 Hz), 8.74 (1H, d, J=2.4 Hz), 11.36 (1H, brs).

(10c)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamideNa salt

The reaction and aftertreatment were conducted in the same manner as inExample 5c by using the5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide(303 mg, 0.643 mmol) prepared in Example 10b, a 1 M sodium hydroxidesolution (0.643 mL, 0.643 mol), to yield the title compound (300 mg,95%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.44-1.60 (3H, m), 1.66-1.77 (1H, m),1.85-1.90 (2H, m), 1.97-2.01 (1H, m), 2.21-2.24 (1H, m), 3.07-3.14 (1H,m), 3.89 (3H, s), 4.36-4.42 (1H, m), 6.15 (1H, d, J=2.0 Hz), 6.28-6.30(1H, m), 6.80 (1H, d, J=11.7 Hz), 7.28 (1H, s), 7.71 (1H, d, J=7.4 Hz),8.54 (1H, d, J=2.4 Hz).

MS (ESI) m/z: 471 [M+H]+

Example 115-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamideNa salt

(11a) Tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate

The reaction and aftertreatment were conducted in the same manner as inExample 1a by usingtert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamate(WO 2010/079443; 600 mg, 1.46 mmol), the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (270 mg, 1.62 mmol)prepared in Example 8a, sodium hydride (63%; 110 mg, 2.89 mmol) and DMF(6.0 mL), to yield the title compound (520 mg, 64%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (9H, s), 1.80-2.01 (4H, m),2.24-2.36 (2H, m), 3.50-3.55 (1H, m), 3.91 (3H, s), 4.67-4.70 (1H, m),6.08 (1H, d, J=2.0 Hz), 6.60 (1H, d, J=11.2 Hz), 7.42 (1H, d, J=1.5 Hz),7.51 (1H, d, J=2.4 Hz), 8.11 (1H, d, J=7.3 Hz), 8.79 (1H, d, J=2.4 Hz).

(11b)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using thetert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate(520 mg, 0.934 mmol) prepared in Example 11a, trifluoroacetic acid (5.0mL) and dichloromethane (5.0 mL), to yield the title compound (427 mg,99%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.78-1.95 (4H, m), 2.18-2.33 (2H, m),3.46-3.50 (1H, m), 3.87 (3H, s), 4.58-4.61 (1H, m), 6.04 (1H, d, J=2.0Hz), 6.51 (1H, d, J=11.2 Hz), 6.92 (1H, s), 7.39 (1H, s), 7.87 (1H, d,J=7.3 Hz), 7.84 (1H, d, J=2.4 Hz), 11.2 (1H, brs).

(11c)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamideNa salt

The reaction and aftertreatment were conducted in the same manner as inExample 5c by using the5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide(427 g, 0.934 mmol) prepared in Example 11b and a 2 M aqueous sodiumhydroxide solution (0.467 mL, 0.934 mol), to yield the title compound(412 mg, 92%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.59-1.71 (2H, m), 1.78-1.84 (2H, m),2.18-2.25 (2H, m), 3.42-3.46 (1H, m), 3.77 (3H, s), 4.84-4.87 (1H, m),5.96-5.98 (1H, m), 6.16 (1H, d, J=2.0 Hz), 6.97 (1H, d, J=11.2 Hz), 7.29(1H, d, J=2.0 Hz), 7.66 (1H, d, J=7.3 Hz), 7.55 (1H, d, J=2.0 Hz).

MS (ESI) m/z: 457 [M+H]+.

Example 125-Chloro-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide

(12a) (1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-ethylpyrazole (2.50 g, 26.0 mmol), butyl lithium(1.63 M solution in hexane; 18.1 mL, 29.5 mmol), cyclohexene oxide (2.97g, 30.3 mmol) and THF (60 mL), to yield the title compound (2.86 g, 57%)as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.30-1.47 (4H, m), 1.43 (3H, t, J=7.4Hz), 1.66 (1H, brs), 1.76-1.79 (1H, m), 1.87-1.90 (2H, m), 2.10-2.13(1H, m), 2.56-2.62 (1H, m), 3.61-3.66 (1H, m), 4.10-4.26 (2H, m), 6.07(1H, d, J=2.0 Hz), 7.47 (1H, d, J=1.6 Hz).

(12b)Tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using thetert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid (WO 2010/079443; 222 mg, 0.540 mmol),(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (100 mg, 0.515 mmol)prepared in Example 12a, sodium hydride (63%; 39.2 mg, 1.03 mmol) andDMF (5.0 mL), to yield the title compound (125 mg, 41%) as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.35 (9H, s), 1.44 (3H, t, J=7.4 Hz),1.44-1.70 (4H, m), 1.87-1.90 (1H, m), 1.96-1.98 (1H, m), 2.05-2.09 (1H,m), 2.24-2.27 (1H, m), 3.04-3.10 (1H, m), 4.12-4.34 (3H, m), 6.04 (1H,s), 6.59 (1H, d, J=11.7 Hz), 7.38 (1H, s), 7.50 (1H, s), 8.01 (1H, d,J=8.6 Hz), 8.79 (1H, s).

(12c)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using thetert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid (125 mg, 0.213 mmol) prepared in Example 12b, trifluoroacetic acid(1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (70.0mg, 68%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41 (3H, t, J=7.0 Hz), 1.46-1.67 (4H,m), 1.84-1.87 (1H, m), 1.91-1.94 (1H, m), 2.03-2.06 (1H, m), 2.19-2.22(1H, m), 3.00-3.06 (1H, m), 4.10-4.21 (2H, m), 4.28-4.37 (1H, m), 6.00(1H, d, J=2.0 Hz), 6.49 (1H, d, J=11.7 Hz), 6.88 (1H, d, J=2.0 Hz), 7.37(1H, d, J=2.0 Hz), 7.80 (1H, d, J=7.4 Hz), 8.75 (1H, d, J=2.0 Hz), 11.40(1H, brs).

MS (ESI) m/z: 485 [M+H]+.

Example 135-chloro-2-fluoro-4-{[(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

(13a)Tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using thetert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid (WO 2010/079443; 390 mg, 0.949 mmol),(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexanol (Heterocycles, 31(3), 537-48,1990; 160 mg, 0.963 mmol), sodium hydride (63%; 75.0 mg, 1.97 mmol) andDMF (4.0 mL), to yield the title compound (340 mg, 64%) as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.36 (9H, s), 1.50-1.65 (3H, m),1.87-2.00 (3H, m), 2.30-2.35 (2H, m), 4.21-4.28 (2H, m), 6.46 (1H, d,J=11.0 Hz), 7.01 (2H, d, J=1.2 Hz), 7.49 (1H, d, J=2.0 Hz), 7.63 (1H,s), 8.03 (1H, d, J=7.4 Hz), 8.78 (1H, d, J=2.4 Hz).

(13b)5-Chloro-2-fluoro-4-{[(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using thetert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamicacid (340 mg, 0.610 mmol) prepared in Example 13a, trifluoroacetic acid(5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (292mg, 67%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.48-1.60 (4H, m), 1.90-1.95 (1H, m),2.03-2.05 (1H, m), 2.25-2.37 (2H, m), 4.30-4.37 (1H, m), 4.65-4.72 (1H,m), 6.70 (1H, d, J=11.0 Hz), 6.93 (1H, d, J=2.4 Hz), 7.25-7.28 (2H, m),7.84 (1H, d, J=7.4 Hz), 8.71 (1H, d, J=2.4 Hz), 9.25 (1H, brs).

MS (ESI) m/z: 457 [M+H]+.

Example 142,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(14a) N-(2,4-dimethoxybenzyl)pyrimidin-4-amine

A solution of 4-aminopyrimidine (20.0 g, 210 mmol),2,4-dimethoxybenzaldehyde (69.9 g, 421 mmol) and piperidine (2.08 mL,21.0 mmol) in toluene (1 L) was stirred for 7 hours under reflux, andthe solvent was subjected to azeotropic distillation with water. Afterallowing to cool, the reaction solution was diluted with ethanol (500mL). Sodium borohydride (7.96 g, 210 mmol) was added thereto withcooling on ice, and the mixture was stirred at room temperature for 16hours. To the reaction solution, water (500 mL) was added, and anorganic layer was extracted. The thus obtained organic layer was driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography (ethylacetate/methanol=95:5) to yield the title compound (27.0 g, 52%) as acolorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.80 (3H, s), 3.84 (3H, s), 4.44 (2H,brs), 5.33 (1H, brs), 6.34 (1H, d, J=5.9 Hz), 6.44 (1H, dd, J=2.4, 8.3Hz), 6.48 (1H, d, J=2.0 Hz), 7.18 (1H, d, J=8.3 Hz), 8.15 (1H, d, J=5.4Hz), 8.55 (1H, s).

(14b)N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.76 g,3.10 mmol) prepared in Example 14a and 1,4-diazabicyclo[2.2.2]octane(0.70 g, 6.20 mmol) in acetonitrile (20 mL),2,4,5-trifluorobenzenesulfonyl chloride (1.43 g, 6.20 mmol) was addedwith cooling on ice, and the reaction solution was stirred at roomtemperature for 1 hour. The reaction solution was filtered, the filtratewas vacuum concentrated, and the residue was purified with silica gelchromatography (hexane/ethyl acetate=67:33) to yield the title compound(0.72 g, 53%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.80 (3H, s), 5.23 (2H, s),6.42-6.43 (2H, m), 6.99-7.04 (1H, m), 7.13 (1H, d, J=5.9 Hz), 7.22 (1H,d, J=9.3 Hz), 7.91-7.96 (1H, m), 8.48 (1H, d, J=6.4 Hz), 8.78 (1H, s).

(14c)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{([(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.76 g, 1.73 mmol) prepared in Example 14b, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.29 g, 1.73 mmol)prepared in Example 8a, sodium hydride (63%; 100 mg, 2.59 mmol) and DMF(10 mL), to yield the title compound (0.89 g, 88%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.78-1.97 (4H, m), 2.20-2.33 (2H, m),3.45-3.49 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 3.86 (3H, s), 4.60-4.64(1H, m), 5.23 (2H, s), 6.05 (1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.52(1H, dd, J=5.9, 10.7 Hz), 7.18-7.20 (2H, m), 7.40 (1H, d, J=2.0 Hz),7.76 (1H, dd, J=6.4, 10.3 Hz), 8.45 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(14d)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.54 g, 1.24 mmol) prepared in Example 14c, triethylsilane (1.98 mL,12.4 mmol), trifluoroacetic acid (0.96 mL, 12.4 mmol) anddichloromethane (20 mL), to yield the title compound (0.54 g, 99%) as acolorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.66-1.83 (4H, m), 2.19-2.27 (2H, m),3.47-3.51 (1H, m), 3.76 (3H, s), 4.92-4.95 (1H, m), 6.17 (1H, s), 6.97(1H, brs), 7.20-7.24 (1H, m), 7.30 (1H, s), 7.68-7.71 (1H, m), 8.25 (1H,brs), 8.57 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 152,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide

(15a)N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide

To a solution of N-(2,4-dimethoxybenzyl)-N-(1,3-thiazol)-2-amine (WO2010/035166; 1.00 g, 4.00 mmol) in THF (12 mL), LiHMDS (1.0 M in THF,4.8 mL, 4.8 mmol) was added at −78° C. The reaction solution was stirredat −78° C. for 5 minutes. Then, 2,4,5-trifluorobenzenesulfonyl chloride(1.05 g, 4.42 mmol) was added thereto, and the mixture was stirred atroom temperature for 2 hours. Water (100 mL) was added to the reactionsolution, followed by extraction with ethyl acetate (50 mL). The thusobtained organic layer was washed twice with water (200 mL) and driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography (hexane/ethyl acetate=4:1)to yield the title compound (960 mg, 54%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 3.73 (3H, s), 3.77 (3H, s), 5.19 (2H, s),6.36-6.39 (2H, m), 7.01-7.07 (2H, m), 7.19 (1H, d, J=8.2 Hz), 7.42 (1H,d, J=3.5 Hz), 7.70-7.76 (1H, m).

(15b)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide(184 mg, 0.414 mmol) prepared in Example 15a,(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (68.7 mg, 0.414mmol) prepared in Example 8a, sodium hydride (63%; 31.6 mg, 0.830 mol)and DMF (2.0 mL), to yield the title compound (180 mg, 73%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.76-1.83 (1H, m), 1.88-1.98 (3H, m),2.19-2.25 (1H, m), 2.27-2.33 (1H, m), 3.44-3.49 (1H, m), 3.73 (3H, s),3.75 (3H, s), 3.86 (3H, s), 4.61-4.64 (1H, m), 5.18 (2H, s), 6.05 (1H,d, J=2.0 Hz), 6.36-6.38 (2H, m), 6.56 (1H, dd, J=6.4, 11.2 Hz), 6.98(1H, d, J=3.4 Hz), 7.19 (1H, d, J=8.3 Hz), 7.38-7.41 (2H, m), 7.58 (1H,dd, J=6.4, 10.3 Hz).

(15c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide(180 mg, 0.305 mmol) prepared in Example 15b, triethylsilane (0.1 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (110 mg, 82%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.77-1.96 (4H, m), 2.19-2.23 (1H, m),2.27-2.32 (1H, m), 3.44-3.48 (1H, m), 3.86 (3H, s), 4.59-4.62 (1H, m),6.05 (1H, s), 6.54-6.57 (2H, m), 7.17 (1H, d, J=4.4 Hz), 7.40 (1H, s),7.71 (1H, dd, J=6.4, 9.8 Hz).

MS (ESI) m/z: 441 [M+H]+.

Example 163-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide

(16a) N-(2,4-dimethoxybenzyl)-3,4-di fluorobenzenesulfonamide

To a solution of 2,4-dimethoxybenzylamine (3.35 mL, 22.3 mmol) andpyridine (9.02 mL, 111.5 mmol) in dichloromethane (75 mL),3,4-difluorobenzenesulfonyl chloride (3.04 mL, 22.3 mmol) was added withcooling on ice, and the reaction solution was stirred at roomtemperature for 16 hours. To the reaction solution, 2 M hydrochloricacid (100 mL) was added, and an organic layer was extracted. The thusobtained organic layer was dried over anhydrous sodium sulfate andvacuum concentrated to yield the title compound (7.66 g, 99%) as acolorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 3.72 (3H, s), 3.77 (3H, s), 4.14 (2H, d,J=6.3 Hz), 5.13 (1H, t, J=5.9 Hz), 6.29 (1H, d, J=2.4 Hz), 6.33 (1H, dd,J=2.4, 8.2 Hz), 6.94 (1H, d, J=8.2 Hz), 7.13-7.19 (1H, m), 7.47-7.53(2H, m).

(16b)N-(2,4-dimethoxybenzyl)-3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-3,4-difluorobenzenesulfonamide (1.00 g, 2.91mmol) prepared in Example 16a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.73 g, 4.37 mmol)prepared in Example 8a, sodium hydride (63%; 0.55 g, 14.6 mmol) and DMF(15 mL), to yield the title compound (920 mg, 65%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.78-1.99 (4H, m), 2.16-2.34 (2H, m),3.43-3.49 (1H, m), 3.69 (3H, s), 3.72 (3H, s), 3.87 (3H, s), 4.08 (2H,d, J=6.3 Hz), 4.64-4.68 (1H, m), 5.24 (1H, t, J=6.3 Hz), 6.07 (1H, d,J=2.0 Hz), 6.26 (1H, d, J=2.0 Hz), 6.30 (1H, dd, J=2.0, 8.2 Hz), 6.73(1H, t, J=8.6 Hz), 6.95 (1H, d, J=8.2 Hz), 7.40-7.43 (3H, m).

MS (ESI) m/z: 490 [M+H]+.

(16c)3-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(0.92 g, 1.88 mmol) prepared in Example 16b, triethylsilane (1.5 mL),trifluoroacetic acid (15 mL) and dichloromethane (15 mL), to yield thetitle compound (0.60 g, 94%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.77-1.97 (4H, m), 2.18-2.36 (2H, m),3.44-3.50 (1H, m), 3.86 (3H, s), 4.70-4.74 (1H, m), 6.07 (1H, d, J=1.6Hz), 6.86 (1H, t, J=8.2 Hz), 7.41 (1H, d, J=2.0 Hz), 7.60-7.64 (2H, m).

(16d)3-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide

A solution of the3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(0.07 g, 0.21 mmol) prepared in Example 16c, 2-bromothiazole (0.07 g,0.41 mmol), copper iodide (0.01 g, 0.04 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (0.01 g, 0.09 mmol) andcesium carbonate (0.20 g, 0.62 mmol) in DMF (2.0 mL) was stirred at 120°C. for 20 hours under the nitrogen atmosphere. After allowing to cool,the reaction solution was vacuum concentrated, and the residue waspurified with HPLC to yield the title compound (75 mg, 86%) as acolorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.78-1.98 (4H, m), 2.20-2.36 (2H, m),3.42-3.49 (1H, m), 3.90 (3H, s), 4.66-4.69 (1H, m), 6.11 (1H, s), 6.54(1H, d, J=6.7 Hz), 6.83 (1H, t, J=8.2 Hz), 7.14 (1H, d, J=4.7 Hz), 7.48(1H, s), 7.58-7.63 (2H, m).

MS (ESI) m/z: 423 [M+H]+.

Example 173-Fluoro-N-(6-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 16d by using the3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(0.07 g, 0.21 mmol) prepared in Example 16c, 4,6-difluoropyrimidine(0.07 g, 0.62 mmol), potassium carbonate (0.11 g, 0.83 mmol) and DMF(2.0 mL), to yield the title compound (56 mg, 63%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.76-1.98 (4H, m), 2.23-2.36 (2H, m),3.44-3.49 (1H, m), 3.85 (3H, s), 4.69-4.72 (1H, m), 6.06 (1H, d, J=1.6Hz), 6.85 (1H, s), 6.88 (1H, t, J=8.2 Hz), 7.41 (1H, d, J=2.0 Hz),7.61-7.67 (2H, m), 8.63 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 183-Fluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 16d by using3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(0.10 g, 0.29 mmol) prepared in Example 16c, 2,4-difluoropyrimidine(0.10 g, 0.88 mmol), potassium carbonate (0.16 g, 1.18 mmol) and DMF(3.0 mL), to yield the title compound (56 mg, 63%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.77-1.96 (4H, m), 2.21-2.32 (2H, m),3.42-3.47 (1H, m), 3.84 (3H, s), 4.68-4.71 (1H, m), 6.06 (1H, d, J=1.6Hz), 6.84 (1H, t, J=8.6 Hz), 7.05 (1H, t, J=3.5 Hz), 7.41 (1H, d, J=2.0Hz), 7.64-7.68 (2H, m), 8.34 (1H, d, J=7.0 Hz).

MS (ESI) m/z: 436 [M+H]+.

Example 192-Chloro-5-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(19a)2-Chloro-N-(2,4-dimethoxybenzyl)-4,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150mg, 0.611 mmol) prepared in Example 14a,2-Chloro-4,5-difluorobenzenesulfonyl chloride (302 mg, 1.22 mmol),1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0mL), to yield the title compound (58.8 mg, 21%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.85 (3H, s), 5.29 (2H, s),6.43-6.46 (2H, m), 6.95 (1H, d, J=7.3 Hz), 7.26-7.31 (2H, m), 8.23 (1H,t, J=8.3 Hz), 8.43 (1H, d, J=5.9 Hz), 8.69 (1H, s).

(19b)2-Chloro-N-(2,4-dimethoxybenzyl)-5-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the2-chloro-N-(2,4-dimethoxybenzyl)-4,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(58.8 mg, 0.129 mmol) prepared in Example 19a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (25.7 mg, 0.155mmol) prepared in Example 8a, sodium hydride (63%; 5.9 mg, 0.155 mmol)and DMF (2.0 mL), to yield the title compound (50.6 mg, 64%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.64-1.99 (4H, m), 2.17-2.34 (2H, m),3.44-3.49 (1H, m), 3.77 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.64-4.67(1H, m), 5.27 (1H, d, J=17.1 Hz), 5.32 (1H, d, J=17.1 Hz), 6.05 (1H, s),6.41-6.45 (2H, m), 6.79 (1H, d, J=6.8 Hz), 7.01 (1H, d, J=5.9 Hz), 7.25(1H, d, J=8.3 Hz), 8.05 (1H, d, J=10.3 Hz), 8.39 (1H, d, J=6.4 Hz), 8.70(1H, s).

(19c)2-Chloro-5-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the2-chloro-N-(2,4-dimethoxybenzyl)-5-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(50.6 mg, 0.0840 mmol) prepared in Example 19b, triethylsilane (0.05mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (15.0 mg, 39%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.78-1.99 (4H, m), 2.23-2.32 (2H, m),3.42-3.48 (1H, m), 3.85 (3H, s), 4.64-4.67 (1H, m), 6.06 (1H, d, J=2.0Hz), 6.85 (1H, d, J=7.3 Hz), 7.05 (1H, d, J=7.3 Hz), 7.39 (1H, s), 7.98(1H, d, J=10.7 Hz), 8.34 (1H, J=5.9 Hz), 8.65 (1H, s).

MS (ESI) m/z: 452 [M+H]+.

Example 205-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(20a)5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (150mg, 0.611 mmol) prepared in Example 14,5-chloro-2,4-difluorobenzenesulfonyl chloride (302 mg, 1.22 mmol),1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0mL), to yield the title compound (71.7 mg, 26%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.79 (3H, s), 5.23 (2H, s),6.41-6.43 (2H, m), 6.98 (1H, d, J=9.3 Hz), 7.16 (1H, d, J=7.3 Hz), 7.22(1H, d, J=8.8 Hz), 8.13 (1H, t, J=7.3 Hz), 8.49 (1H, d, J=5.9 Hz), 8.79(1H, s).

(20b)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(71.7 mg, 0.157 mmol) prepared in Example 20a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (31.1 mg, 0.187mmol) prepared in Example 8a, sodium hydride (63%; 7.1 mg, 0.186 mmol)and DMF (2.0 mL), to yield the title compound (79.1 mg, 84%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.73-1.98 (4H, m), 2.17-2.35 (2H, m),3.48-3.52 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.88 (3H, s), 4.60-4.63(1H, m), 5.22 (1H, d, J=17.1 Hz), 5.26 (1H, d, J=17.1 Hz), 6.06 (1H, d,J=1.5 Hz), 6.39-6.41 (2H, m), 6.48 (1H, d, J=11.7 Hz), 7.18-7.21 (2H,m), 7.40 (1H, s), 8.02 (1H, d, J=7.3 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79(1H, s).

(20c)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(79.1 mg, 0.131 mmol) prepared in Example 20b, triethylsilane (0.05 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (30.0 mg, 51%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.79-1.96 (4H, m), 2.20-2.33 (2H, m),3.48-3.52 (1H, m), 3.89 (3H, s), 4.60-4.63 (1H, m), 6.05 (1H, s), 6.54(1H, d, J=11.7 Hz), 7.26-7.27 (1H, m), 7.39 (1H, s), 8.02 (1H, d, J=7.3Hz), 8.39 (1H, J=4.9 Hz), 8.81 (1H, s).

MS (ESI) m/z: 452 [M+H]+.

Example 214-{[(1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide

(21a)N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150mg, 0.611 mmol) prepared in Example 14a,4-fluoro-3-(trifluoromethyl)benzenesulfonyl chloride (321 mg, 1.22mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) andacetonitrile (5.0 mL), to yield the title compound (94.7 mg, 33%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.65 (3H, s), 3.78 (3H, s), 5.16 (2H, s),6.36 (1H, s), 6.40 (1H, d, J=8.3 Hz), 7.12-7.14 (2H, m), 7.27-7.30 (1H,m), 8.14-8.16 (2H, m), 8.53 (1H, d, J=5.9 Hz), 8.55 (1H, s).

(21b)N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide(94.7 mg, 0.201 mmol) prepared in Example 21a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (40.1 mg, 0.241mmol) prepared in Example 8a, sodium hydride (63%; 9.2 mg, 0.241 mmol)and DMF (2.0 mL), to yield the title compound (123 mg, 99%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.62-1.94 (4H, m), 2.10-2.35 (2H, m),3.44-3.47 (1H, m), 3.70 (3H, s), 3.76 (3H, s), 3.80 (3H, s), 4.80-4.82(1H, m), 5.17 (2H, s), 6.07 (1H, d, J=2.0 Hz), 6.37-6.39 (2H, m), 6.84(1H, d, J=8.8 Hz), 7.10 (1H, d, J=9.3 Hz), 7.16 (1H, d, J=6.8 Hz), 7.38(1H, d, J=2.0 Hz), 7.99 (1H, dd, J=2.4, 8.8 Hz), 8.08 (1H, d, J=2.0 Hz),8.47 (1H, d, J=5.9 Hz), 8.82 (1H, s).

(21c)4-{[(1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide(123 mg, 0.199 mmol) prepared in Example 21b, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (50.0 mg, 54%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.76-1.97 (4H, m), 2.15-2.36 (2H, m),3.43-3.47 (1H, m), 3.80 (3H, s), 4.80-4.82 (1H, m), 6.07 (1H, s), 6.90(1H, d, J=8.8 Hz), 7.20 (1H, d, J=5.9 Hz), 7.42 (1H, s), 8.04 (1H, dd,J=2.4, 8.8 Hz), 8.16 (1H, J=2.0 Hz), 8.44 (1H, d, J=5.4 Hz), 8.82 (1H,s).

MS (ESI) m/z: 468 [M+H]+.

Example 222,5-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(22a)(1S*,2R*)-2-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 8a by using 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (5.50 g,36.1 mmol), n-butyl lithium (1.63 M solution in hexane; 24 mL, 39.1mmol), cyclohexene oxide (3.80 g, 38.7 mmol) and THF (100 mL), to yieldthe title compound (270 mg, 3.0%) in the form of a diastereomericmixture as a colorless oil.

(22b)N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclohexyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(360 mg, 0.819 mmol) prepared in Example 14b, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclohexanol(202 mg, 0.807 mmol) prepared in Example 22a, sodium hydride (63%; 50mg, 1.32 mmol) and DMF (4.0 mL), to yield the title compound (366 mg,68%) in the form of a diastereomeric mixture as a colorless oil.

(22c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of theN-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclohexyl}oxy)benzenesulfonamide(366 mg, 0.547 mmol) prepared in Example 22b and triethylsilane (0.40mL) in dichloromethane (4.0 mL), trifluoroacetic acid (4.0 mL) was addedat room temperature, and the reaction solution was stirred for 1 hour.To the reaction solution, methanol (4.0 mL) was added, and the mixturewas further stirred at room temperature for 1 hour. The reactionsolution was concentrated, and the residue was purified with silica gelchromatography (dichloromethane/methanol=95:5) to yield the titlecompound (182 mg, 61%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.32-1.77 (6H, m), 1.90-1.92 (1H, m),2.10-2.23 (1H, m), 2.91-2.96 (1H, m), 4.64-4.68 (1H, m), 6.06 (1H, d,J=2.0 Hz), 6.96 (1H, brs), 7.22-7.26 (1H, m), 7.38 (1H, s), 7.57-7.60(1H, m), 8.25 (1H, brs), 8.58 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 233-Chloro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(23a)3-Chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150mg, 0.611 mmol) prepared in Example 14a,3-chloro-4-fluorobenzenesulfonyl chloride (280 mg, 1.22 mmol),1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0mL), to yield the title compound (127 mg, 47%) as a colorless amorphoussolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.68 (3H, s), 3.78 (3H, s), 5.18 (2H, s),6.39 (1H, s), 6.41 (1H, d, J=10.3 Hz), 7.13-7.27 (3H, m), 7.80-7.83 (1H,m), 7.87 (1H, d, J=8.8 Hz), 8.51 (1H, d, J=5.9 Hz), 8.86 (1H, s).

(23b)3-Chloro-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(127 mg, 0.290 mmol) prepared in Example 23a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (50.6 mg, 0.304mmol) prepared in Example 8a, sodium hydride (63%; 16.6 mg, 0.435 mmol)and DMF (2.0 mL), to yield the title compound (123 mg, 73%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.78-1.99 (4H, m), 2.20-2.34 (2H, m),3.47-3.51 (1H, m), 3.72 (3H, s), 3.76 (3H, s), 3.88 (3H, s), 4.68-4.71(1H, m), 5.19 (2H, s), 6.07 (1H, d, J=2.0 Hz), 6.38-6.40 (2H, m), 6.76(1H, d, J=9.3 Hz), 7.13 (1H, d, J=8.3 Hz), 7.23 (1H, dd, J=2.0, 5.9 Hz),7.41 (1H, d, J=2.0 Hz), 7.70 (1H, dd, J=2.0, 8.8 Hz), 7.80 (1H, d, J=2.4Hz), 8.47 (1H, d, J=5.9 Hz), 8.83 (1H, s).

(23c)3-Chloro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the3-chloro-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(123 mg, 0.211 mmol) prepared in Example 23b, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (85.0 mg, 54%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.79-1.97 (4H, m), 2.20-2.32 (2H, m),3.46-3.50 (1H, m), 3.86 (3H, s), 4.70-4.72 (1H, m), 6.07 (1H, s), 6.80(1H, d, J=8.8 Hz), 7.17 (1H, d, J=5.4 Hz), 7.40 (1H, s), 7.79 (1H, dd,J=2.4, 8.8 Hz), 7.97 (1H, J=2.4 Hz), 8.41 (1H, brs), 8.77 (1H, s).

MS (ESI) m/z: 434 [M+H]+.

Example 242,5-Difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

(24a) N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine

A solution of 2,4-difluoropyrimidine (600 mg, 5.17 mmol) and2,4-dimethoxybenzylamine (860 mg, 5.17 mmol) in THF (17 mL) was stirredat room temperature for 1 hour. The reaction solution was vacuumconcentrated, and the residue was then purified with silica gelchromatography (hexane/ethyl acetate=1:2) to yield the title compound(594 mg, 43%) as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 3.74 (3H, s), 3.80 (3H, s), 4.36 (2H,d, J=5.5 Hz), 6.47-6.50 (2H, m), 6.58 (1H, d, J=2.4 Hz), 7.13 (1H, d,J=8.6 Hz), 7.89-7.91 (1H, m), 8.19 (1H, brs).

(24b)N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(2-fluoropyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 15a by using theN-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine (0.20 g, 0.76 mmol)prepared in Example 24a, LiHMDS (1.0 M in THF, 0.91 mL, 0.91 mmol),2,4,5-trifluorobenzenesulfonyl chloride (0.19 g, 0.84 mmol) and THF (3.0mL), to yield the title compound (0.22 g, 63%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.79 (3H, s), 3.81 (3H, s), 5.23 (2H, s),6.43-6.45 (2H, m), 7.01-7.06 (2H, m), 7.23 (1H, d, J=7.8 Hz), 7.97 (1H,q, J=8.3 Hz), 7.34 (1H, dd, J=2.0, 5.9 Hz).

(24c)N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(2-fluoropyrimidin-4-yl)benzenesulfonamide(0.10 g, 0.23 mmol) prepared in Example 24b, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.04 g, 0.23 mmol)prepared in Example 8a, sodium hydride (63%; 0.01 g, 0.28 mmol) and DMF(1.0 mL), to yield the title compound (648 mg, 46%) as a colorlessamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.76-1.98 (4H, m), 2.21-2.36 (2H, m),3.45-3.50 (1H, m), 3.77 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 4.61-4.65(1H, m), 5.22 (2H, s), 6.06 (1H, d, J=2.0 Hz), 6.42-6.44 (2H, m), 6.54(1H, dd, J=6.3, 11.0 Hz), 7.09 (1H, dd, J=3.5, 5.9 Hz), 7.21 (1H, d,J=9.0 Hz), 7.41 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=6.7, 10.2 Hz), 8.31(1H, dd, J=2.0, 5.5 Hz).

(24d)2,5-Difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(648 mg, 0.13 mmol) prepared in Example 24c, triethylsilane (0.11 mL),trifluoroacetic acid (0.13 g) and dichloromethane (1.3 mL), to yield thetitle compound (0.06 g, 78%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.75-1.98 (4H, m), 2.26-2.35 (2H, m),3.50-3.55 (1H, m), 3.80 (3H, s), 4.83-4.88 (1H, m), 6.19 (1H, d, J=2.0Hz), 6.87 (1H, dd, J=3.9, 5.9 Hz), 6.94 (1H, dd, J=6.7, 11.3 Hz), 7.35(1H, d, J=2.0 Hz), 7.78 (1H, dd, J=6.7, 10.6 Hz), 8.24 (1H, dd, J=2.4,5.9 Hz).

MS (ESI) m/z: 454 [M+H]+.

Example 252,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(25a)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(244 mg, 0.555 mmol) prepared in Example 14b, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (100 mg, 0.555 mmol)prepared in Example 4a, sodium hydride (63%; 31.7 mg, 0.793 mmol) andDMF (3 mL), to yield the title compound (268 mg, 80%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.68 (4H, m), 1.86-1.96 (2H, m),2.04-2.07 (1H, m), 2.22-2.25 (1H, m), 2.98-3.03 (1H, m), 3.76 (3H, s),3.77 (3H, s), 3.91 (3H, s), 4.08-4.14 (1H, m), 5.19 (1H, d, J=17.1 Hz),5.23 (1H, d, J=16.6 Hz), 6.02 (1H, d, J=2.0 Hz), 6.39-6.40 (2H, m), 6.47(1H, dd, J=6.4, 11.2 Hz), 7.17-7.19 (2H, m), 7.33 (1H, d, J=1.5 Hz),7.67 (1H, dd, J=6.4, 9.8 Hz), 8.45 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(25b)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(268 mg, 0.447 mmol) prepared in Example 25a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (130 mg, 65%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-1.68 (4H, m), 1.86-1.89 (1H, m),1.93-1.95 (1H, m), 2.05-2.07 (1H, m), 2.22-2.25 (1H, m), 2.97-3.02 (1H,m), 3.90 (3H, s), 4.07-4.12 (1H, m), 6.02 (1H, d, J=2.0 Hz), 6.50 (1H,dd, J=6.4, 11.2 Hz), 7.24 (1H, d, J=6.4 Hz), 7.33 (1H, d, J=2.0 Hz),7.66 (1H, dd, J=6.8, 10.3 Hz), 8.38 (1H, d, J=6.4 Hz), 8.80 (1H, s).

MS (ESI) m/z: 450 [M+H]+.

Example 263-Cyano-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(26a)3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (600mg, 2.44 mmol) prepared in Example 14a, 3-cyano-4-fluorobenzenesulfonylchloride (1.07 g, 4.87 mmol), 1,4-diazabicyclo[2.2.2]octane (549 mg,4.89 mmol) and acetonitrile (12 mL), to yield the title compound (200mg, 19%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.60 (3H, s), 3.80 (3H, s), 5.15 (2H, s),6.36 (1H, d, J=2.4 Hz), 6.45 (1H, dd, J=2.4, 8.3 Hz), 7.11 (1H, dd,J=1.0, 5.9 Hz), 7.16 (1H, d, J=8.3 Hz), 7.30 (1H, t, J=8.8 Hz), 8.01(1H, dd, J=2.0, 5.4 Hz), 8.20-8.23 (1H, m), 8.55 (1H, d, J=5.9 Hz), 8.87(1H, s).

(26b)3-Cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(200 mg, 0.47 mmol) prepared in Example 26a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (81.5 mg, 0.49 mmol)prepared in Example 8a, sodium hydride (63%; 26.7 mg, 0.70 mmol) and DMF(2.0 mL), to yield the title compound (91.0 mg, 34%) as a colorlesssolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.79-2.01 (4H, m), 2.24-2.36 (2H, m),3.50-3.54 (1H, m), 3.67 (3H, s), 3.78 (3H, s), 3.89 (3H, s), 4.75-4.78(1H, m), 5.15 (2H, s), 6.07 (1H, d, J=2.0 Hz), 6.38-6.42 (2H, m), 6.82(1H, d, J=9.3 Hz), 7.11-7.13 (2H, m), 7.42 (1H, d, J=1.5 Hz), 7.97 (1H,d, J=2.4 Hz), 8.03 (1H, dd, J=2.4, 8.8 Hz), 8.50 (1H, d, J=5.9 Hz), 8.84(1H, s).

(26c)3-Cyano-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(91.0 mg, 0.16 mmol) prepared in Example 26b, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (53.3 mg, 79%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.80-1.99 (4H, m), 2.25-2.36 (2H, m),3.50-3.54 (1H, m), 3.89 (3H, s), 4.76-4.79 (1H, m), 6.08 (1H, s), 6.89(1H, d, J=9.3 Hz), 7.14 (1H, d, J=5.4 Hz), 7.42 (1H, s), 8.09 (1H, dd,J=2.4, 8.8 Hz), 8.17 (1H, d, J=2.4 Hz), 8.39 (1H, s), 8.75 (1H, s).

MS (ESI) m/z: 425 [M+H]+.

Example 272,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(27a)N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (600mg, 2.44 mmol) prepared in Example 14a, 2,4,6-trifluorobenzenesulfonylchloride (1.50 g, 6.51 mmol), 1,4-diazabicyclo[2.2.2]octane (549 mg,4.89 mmol) and acetonitrile (12 mL), to yield the title compound (192mg, 18%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.73 (3H, s), 5.26 (2H, s),6.42-6.46 (2H, m), 6.78 (2H, t, J=8.3 Hz), 7.07 (1H, dd, J=1.5, 5.9 Hz),7.24 (1H, d, J=8.8 Hz), 8.46 (1H, d, J=6.4 Hz), 8.78 (1H, s).

(27b)N-(2,4-Dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(192 mg, 0.44 mmol) prepared in Example 27a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (76.3 mg, 0.46 mmol)prepared in Example 8a, sodium hydride (63%; 25.0 mg, 0.66 mmol) and DMF(2.0 mL), to yield the title compound (192 mg, 75%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) 5 ppm: 1.72-1.95 (4H, m), 2.17-2.32 (2H, m),3.35-3.39 (1H, m), 3.77 (3H, s), 3.82 (6H, s), 4.62-4.65 (1H, m), 5.27(2H, s), 6.04 (1H, d, J=2.0 Hz), 6.39-6.44 (4H, m), 7.16 (1H, d, J=7.3Hz), 7.22 (1H, d, J=7.3 Hz), 7.41 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=5.9Hz), 8.78 (1H, s).

(27c)2,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(192 mg, 0.33 mmol) prepared in Example 27b, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (106 mg, 74%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.72-1.95 (4H, m), 2.17-2.31 (2H, m),3.35-3.39 (1H, m), 3.82 (3H, s), 4.61-4.64 (1H, m), 6.04 (1H, d, J=2.0Hz), 6.41 (2H, d, J=10.7 Hz), 7.40-7.42 (2H, m), 8.42 (1H, d, J=5.9 Hz),8.87 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 284-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(28a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(270 mg, 0.615 mmol) prepared in Example 14b, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (120 mg, 0.618 mmol)prepared in Example 12a, sodium hydride (63%; 50 mg, 1.31 mmol) and DMF(3 mL), to yield the title compound (220 mg, 58%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.66 (4H, m), 1.43 (3H, t, J=7.3Hz), 1.85-1.88 (1H, m), 1.94-1.96 (1H, m), 2.03-2.06 (1H, m), 2.22-2.25(1H, m), 2.97-3.03 (1H, m), 3.76 (3H, s), 3.77 (3H, s), 4.12-4.32 (3H,m), 5.19 (1H, d, J=16.6 Hz), 5.23 (1H, d, J=17.1 Hz), 6.00 (1H, d, J=2.0Hz), 6.38-6.40 (2H, m), 6.47 (1H, dd, J=6.4, 11.2 Hz), 7.17-7.19 (2H,m), 7.36 (1H, d, J=1.5 Hz), 7.66 (1H, dd, J=6.8, 10.3 Hz), 8.45 (1H, d,J=5.9 Hz), 8.78 (1H, s).

(28b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(220 mg, 0.359 mmol) prepared in Example 28a, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (160 mg, 96%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.37 (3H, t, J=7.3 Hz), 1.43-1.73 (4H,m), 1.81-1.83 (1H, m), 1.89-1.91 (1H, m), 1.96-1.99 (1H, m), 2.23-2.25(1H, m), 3.06-3.11 (1H, m), 4.11-4.18 (1H, m), 4.26-4.33 (1H, m),4.46-4.50 (1H, m), 6.14 (1H, d, J=2.0 Hz), 6.97 (1H, dd, J=6.8, 11.7Hz), 7.01 (1H, d, J=7.3 Hz), 7.27 (1H, d, J=2.0 Hz), 7.64 (1H, dd,J=6.4, 10.3 Hz), 8.26 (1H, d, J=6.4 Hz), 8.54 (1H, s).

MS (ESI) m/z: 464 [M+H]+.

Example 292-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(29a)N-(2,4-Dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (0.40g, 1.63 mmol) prepared in Example 14a, 2,4-difluorobenzenesulfonylchloride (0.69 g, 3.26 mmol), 1,4-diazabicyclo[2.2.2]octane (0.37 g,3.26 mmol) and acetonitrile (11 mL), to yield the title compound (403.8mg, 59%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 3.77 (3H, s), 3.80 (3H, s), 5.26 (2H, s),6.41-6.44 (2H, m), 6.87-6.92 (1H, m), 7.01-7.06 (1H, m), 7.16 (1H, dd,J=1.6, 5.9 Hz), 7.22 (1H, d, J=8.2 Hz), 8.12 (1H, dt, J=5.9, 8.6 Hz),8.45 (1H, d, J=5.9 Hz), 8.75 (1H, d, J=1.2 Hz).

(29b)N-(2,4-Dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.40 g, 0.95 mmol) prepared in Example 29a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.16 g, 0.95 mmol)prepared in Example 8a, sodium hydride (63%; 0.040 g, 1.14 mmol) and DMF(5.0 mL), to yield the title compound (268.5 mg, 50%) as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.59-1.99 (4H, m), 2.17-2.33 (2H, m),3.35-3.40 (1H, m), 3.76 (3H, s), 3.80 (3H, s), 3.82 (3H, s), 4.65-4.69(1H, m), 5.26 (2H, s), 6.05 (1H, d, J=2.0 Hz), 6.39-6.43 (2H, m), 6.53(1H, dd, J=2.4, 12.1 Hz), 6.67 (1H, dd, J=2.4, 9.0 Hz), 7.17-7.23 (2H,m), 7.37-7.41 (1H, m), 7.94 (1H, t, J=8.6 Hz), 8.41 (1H, d, J=5.5 Hz),8.75 (1H, d, J=0.8 Hz).

(29C)2-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.27 g, 0.47 mmol) prepared in Example 29b, triethylsilane (0.38 mL,2.36 mmol), trifluoroacetic acid (0.47 g, 0.44 mmol) and dichloromethane(5.0 mL), to yield the title compound (0.21 g, 22%) as a colorlesssolid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.76-1.95 (4H, m), 2.26-2.33 (2H, m),3.45-3.49 (1H, m), 3.80, (3H, s), 4.86-4.91 (1H, m), 6.24 (1H, d, J=2.4Hz), 6.77-6.86 (2H, m), 7.15 (1H, d, J=7.4 Hz), 7.43 (1H, d, J=2.0 Hz),7.95 (1H, t, J=8.6 Hz), 8.40 (1H, d, J=5.9 Hz), 8.68 (1H, s).

MS (ESI) m/z: 418 [M+H]+.

Example 302,3-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(30a)N-(2,4-Dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (400mg, 1.63 mmol) prepared in Example 14a, 2,3,4-trifluorobenzenesulfonylchloride (752 mg, 3.26 mmol), 1,4-diazabicyclo[2.2.2]octane (366 mg,3.26 mmol) and acetonitrile (8.0 mL), to yield the title compound (221mg, 31%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.80 (3H, s), 5.24 (2H, s),6.42-6.44 (2H, m), 7.11-7.16 (2H, m), 7.22 (1H, d, J=7.8 Hz), 7.84-7.89(1H, m), 8.48 (1H, d, J=5.9 Hz), 8.76 (1H, s).

(30b)N-(2,4-Dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(190 mg, 0.43 mmol) prepared in Example 30a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (75.5 mg, 0.45 mmol)prepared in Example 8a, sodium hydride (63%; 24.7 mg, 0.65 mmol) and DMF(2.0 mL), to yield the title compound (190 mg, 75%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.77-1.97 (4H, m), 2.22-2.34 (2H, m),3.44-3.48 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 3.85 (3H, s), 4.72-4.75(1H, m), 5.24 (1H, d, J=17.1 Hz), 5.28 (1H, d, J=16.6 Hz), 6.07 (1H, d,J=2.0 Hz), 6.39-6.42 (2H, m), 6.64 (1H, t, J=8.8 Hz), 7.19-7.21 (2H, m),7.41 (1H, d, J=2.0 Hz), 7.71 (1H, t, J=8.8 Hz), 8.45 (1H, d, J=5.9 Hz),8.76 (1H, s).

(30c)2,3-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(190 mg, 0.32 mmol) prepared in Example 30b, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (58.5 mg, 41%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.77-1.96 (4H, m), 2.20-2.34 (2H, m),3.44-3.48 (1H, m), 3.84 (3H, s), 4.71-4.74 (1H, m), 6.06 (1H, d, J=1.5Hz), 6.66 (1H, t, J=7.8 Hz), 7.24-7.25 (1H, m), 7.41 (1H, s), 7.70 (1H,t, J=9.3 Hz), 8.37 (1H, d, J=6.4 Hz), 8.81 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 312,5-Difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(31a)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

TheN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamideprepared in Example 14c was optically resolved with CHIRALPAK AD (DaicelCorp.; hexane/isopropanol=4:1) to yield the title compound as acolorless oil.

(31b)2,5-Difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(411 mg, 0.70 mmol) prepared in Example 31a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (241 mg, 79%) as a colorless solid.

[α]_(D) ²⁵=58.9 (c 1.02, DMSO).

Example 322,5-Difluoro-4-{[(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(32a)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(260 mg, 0.592 mmol) prepared in Example 14b,(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexanol (Tetrahedron, 2007, 63,469-473; 100 mg, 0.602 mmol), sodium hydride (63%; 50 mg, 1.31 mmol) andDMF (3.0 mL), to yield the title compound (315 mg, 91%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.43-1.63 (3H, m), 1.82-1.97 (3H, m),2.26-2.31 (2H, m), 3.77 (3H, s), 3.78 (3H, s), 4.14-4.17 (2H, m), 5.19(1H, d, J=16.6 Hz), 5.23 (1H, d, J=17.1 Hz), 6.35 (1H, dd, J=5.9, 10.7Hz), 6.39-6.41 (2H, m), 6.96 (2H, s), 7.16-7.19 (2H, m), 7.58 (1H, s),7.68 (1H, dd, J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(32b)2,5-Difluoro-4-{[(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(315 mg, 0.538 mmol) prepared in Example 32a, triethylsilane (0.40 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (220 mg, 94%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.55-1.62 (3H, m), 1.91-1.96 (2H, m),2.05-2.13 (1H, m), 2.26-2.28 (1H, m), 2.36-2.38 (1H, m), 4.60-4.71 (2H,m), 6.99 (1H, d, J=6.4 Hz), 7.06 (1H, dd, J=6.4, 11.2 Hz), 7.48 (1H, s),7.69 (1H, dd, J=6.4, 10.3 Hz), 7.76 (1H, s), 8.23 (1H, d, J=6.4 Hz),8.52 (1H, s), 9.03 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 332,5-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(33a) 4-Cyclohex-1-en-1-yl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A solution of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J. Org.Chem. 2007, 72, 3589-3591; 2.00 g, 7.19 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 g,7.21 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(300 mg, 0.41 mmol) and potassium carbonate (3.00 g, 21.7 mmol) in DMF(13 mL) was stirred at 90° C. for 3 hours under microwave irradiation.After allowing to cool, water (50 mL) was added to the reactionsolution, followed by extraction with ethyl acetate (50 mL). The thusobtained organic layer was washed twice with water (100 mL) and driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with column chromatography (hexane/ethyl acetate=9:1) toyield the title compound (637 mg, 38%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.58-1.76 (8H, m), 2.03-2.05 (2H, m),2.08-2.16 (2H, m), 2.25-2.28 (2H, m), 3.69 (1H, dt, J=2.4, 11.2 Hz),4.04-4.07 (1H, m), 5.34 (1H, dd, J=2.4, 9.8 Hz), 6.00-6.02 (1H, m), 6.96(1H, brs), 7.52 (1H, s), 7.61 (1H, s).

(33b)(1S*,2R*)-2-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol

To a solution of the4-cyclohex-1-en-1-yl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (775 mg,3.34 mmol) prepared in Example 33a in THF (4 mL), a borane-THF complex(0.95 M; 3.4 mL, 3.23 mmol) was added with cooling on ice, and thereaction solution was stirred for 30 minutes with cooling on ice. To thereaction solution, a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) wasadded again, and the mixture was stirred at room temperature for 90minutes. To the reaction solution, water (5 mL) and subsequently sodiumperborate tetrahydrate (1.00 g, 6.50 mmol) were added, and the mixturewas stirred for 5 hours. To the reaction solution, sodium thiosulfate(2.0 g) was added, followed by extraction with ethyl acetate (50 mL).The thus obtained organic layer was dried over anhydrous sodium sulfate.After vacuum concentration, the residue was purified with columnchromatography (dichloromethane/methanol=97:3) to yield the titlecompound (590 mg, 71%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.24-1.94 (10H, m), 2.05-2.14 (4H, m),2.37-2.43 (1H, m), 3.38-3.44 (1H, m), 3.67-3.73 (1H, m), 4.07 (1H, dd,J=3.9, 11.7 Hz), 5.34 (1H, dd, J=2.7, 9.8 Hz), 7.49 (1H, s), 7.50 (1H,s).

(33c)N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(340 mg, 0.774 mmol) prepared in Example 14b, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(198 mg, 0.791 mmol) prepared in Example 33b, sodium hydride (63%; 50mg, 1.31 mmol) and DMF (4.0 mL), to yield the title compound (302 mg,58%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.40-1.67 (8H, m), 1.82-2.17 (6H, m),2.85-2.90 (1H, m), 3.63-3.67 (1H, m), 3.76 (3H, s), 3.78 (3H, s),3.97-4.01 (2H, m), 5.22 (2H, s), 5.25-5.29 (1H, m), 6.39-6.41 (2H, m),6.46-6.50 (1H, m), 7.17-7.20 (2H, m), 7.43-7.46 (2H, m), 7.69 (1H, dd,J=6.4, 9.8 Hz), 8.45 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(33d)2,5-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-(N-pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide(302 mg, 0.451 mmol) prepared in Example 33c, triethylsilane (0.40 mL),trifluoroacetic acid (4.0 mL), dichloromethane (4.0 mL) and methanol(4.0 mL), to yield the title compound (246 mg, 55%) as a colorlesssolid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.37-1.57 (3H, m), 1.65-1.72 (1H, m),1.78-1.81 (1H, m), 1.85-1.87 (1H, m), 2.03-2.05 (1H, m), 2.15-2.19 (1H,m), 2.82-2.88 (1H, m), 4.26-4.31 (1H, m), 6.94 (1H, dd, J=6.8, 12.2 Hz),7.02 (1H, d, J=5.4 Hz), 7.45 (2H, s), 7.66 (1H, dd, J=6.8, 10.3 Hz),8.26 (1H, d, J=6.4 Hz), 8.54 (1H, s).

MS (ESI) m/z: 436 [M+H]+.

Example 344-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(34a)4-Cyclohex-1-en-1-yl-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 33a by using4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (WO2010/079443; 1.20 g, 4.35 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.20 g,5.77 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(250 mg, 0.342 mmol), potassium carbonate (2.00 g, 14.5 mmol) and DMF(13 mL), to yield the title compound (950 mg, 79%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.64-1.76 (8H, m), 1.99-2.06 (2H, m),2.14-2.18 (2H, m), 2.21-2.24 (2H, m), 3.69-3.74 (1H, m), 4.05-4.08 (1H,m), 5.40 (1H, dd, J=2.9, 9.3 Hz), 5.84-5.86 (1H, m), 7.52 (1H, s).

(34b)(1S*,2R*)-2-[3-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the4-cyclohex-1-en-1-yl-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(950 mg, 3.43 mmol) prepared in Example 34a, a borane-THF complex (0.95M; 8.0 mL, 7.60 mmol), sodium perborate tetrahydrate (1.10 g, 7.15mmol), THF (5.0 mL) and water (7.0 mL), to yield the title compound (320mg, 32%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.31-1.86 (8H, m), 2.01-2.17 (6H, m),3.11-3.16 (1H, m), 3.50-3.55 (1H, m), 3.68-3.73 (1H, m), 4.04-4.09 (1H,m), 5.38-5.42 (1H, m), 7.62 (1H, s).

(34c)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(240 mg, 0.546 mmol) prepared in Example 14b, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(160 mg, 0.542 mmol) prepared in Example 34b, sodium hydride (63%; 50mg, 1.31 mmol) and DMF (3.0 mL), to yield the title compound (310 mg,80%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.45-1.69 (8H, m), 1.81-2.23 (6H, m),3.54-3.59 (1H, m), 3.61-3.70 (1H, m), 3.77 (3H, s), 3.79 (3H, s),3.95-4.01 (1H, m), 4.28-4.33 (1H, m), 5.22 (2H, s), 5.30-5.36 (1H, m),6.40-6.41 (2H, m), 6.56-6.51 (1H, m), 7.18-7.20 (2H, m), 7.49 (1H, d,J=12.2 Hz), 7.64-7.69 (1H, m), 7.46 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(34d)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

A solution of theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(310 mg, 0.434 mmol) prepared in Example 34c, an iron powder (300 mg,5.37 mol) and a saturated aqueous solution of ammonium chloride (5.0 mL)in ethanol (10 mL) was heated under reflux with stirring for 1 hour.After allowing to cool, the reaction solution was filtered throughcelite, and the filtrate was subjected to extraction withdichloromethane (100 mL). The organic layer was dried over anhydroussodium sulfate and vacuum concentrated to yield crude amine. To asolution of the crude amine and triethylsilane (0.30 mL) indichloromethane (3.0 mL), trifluoroacetic acid (3.0 mL) was added atroom temperature, and the reaction solution was stirred for 1 hour. Tothe reaction solution, methanol (3.0 mL) was added, and the mixture wasfurther stirred at room temperature for 1 hour. The reaction solutionwas concentrated, and the residue was purified with silica gelchromatography (dichloromethane/methanol=90:10) to yield the titlecompound (41.1 mg, 21%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.41-1.56 (3H, m), 1.64-1.73 (1H, m),1.81-1.84 (1H, m), 1.87-1.89 (1H, m), 1.96-1.99 (1H, m), 2.21-2.23 (1H,m), 2.80-2.85 (1H, m), 4.34-4.39 (1H, m), 7.00-7.03 (2H, m), 7.58 (1H,brs), 7.69 (1H, dd, J=6.4, 10.3 Hz), 8.26 (1H, d, J=5.9 Hz), 8.53 (1H,s).

MS (ESI) m/z: 451 [M+H]+.

Example 354-{[(1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(35a) 4-Cyclohex-1-en-1-ylpyridin-2-amine

The reaction and aftertreatment were conducted in the same manner as inExample 33a by using 2-amino-4-chloropyridine (927 mg, 7.21 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 g,7.21 mmol), tetrakis(triphenylphosphine)palladium (0) (416 mg, 0.360mmol), potassium carbonate (3.98 g, 14.5 mmol) and DMF (13 mL), to yieldthe title compound (180 mg, 14%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.63-1.68 (2H, m), 1.74-1.79 (2H, m),2.17-2.22 (2H, m), 2.31-2.34 (2H, m), 4.39 (2H, brs), 6.27-6.29 (1H, m),6.46 (1H, s), 6.68 (1H, dd, J=1.5, 5.4 Hz), 7.98 (1H, d, J=5.9 Hz).

(35b) (1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the 4-cyclohex-1-en-1-ylpyridin-2-amine (180 mg,1.03 mmol) prepared in Example 35a, a borane-THF complex (0.95 M; 5.17mL, 4.91 mmol), sodium perborate tetrahydrate (159 mg, 1.03 mmol), THF(5.0 mL) and water (5.0 mL), to yield the title compound (27.0 mg, 14%)as a brown solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.25-1.84 (4H, m), 1.95-2.21 (4H, m),2.30-2.36 (1H, m), 3.62-3.69 (1H, m), 4.62 (2H, brs), 6.40 (1H, s), 6.56(1H, d, J=4.4 Hz), 7.92 (1H, brs).

(35c)4-{[(1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(64.8 mg, 0.147 mmol) prepared in Example 14b, the(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclohexanol (27.0 mg, 0.140 mmol)prepared in Example 35b, sodium hydride (63%; 8.0 mg, 0.210 mmol) andDMF (2.0 mL), to yield the title compound (42.7 mg, 50%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.37-1.69 (4H, m), 1.82-1.85 (1H, m),1.92-1.98 (2H, m), 2.23 (1H, d, J=12.3 Hz), 2.73-2.79 (1H, m), 3.76 (3H,s), 3.77 (3H, s), 4.25 (1H, dt, J=4.4, 10.7 Hz), 4.36 (2H, brs), 5.21(2H, s), 6.36-6.40 (3H, m), 6.52-6.54 (2H, m), 7.17-7.20 (2H, m), 7.64(1H, dd, J=6.4, 9.8 Hz), 7.93 (1H, d, J=4.9 Hz), 8.45 (1H, d, J=5.9 Hz),8.78 (1H, s).

(35d)4-{[(1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(42.7 mg, 0.0698 mmol) prepared in Example 35c, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (18.6 mg, 58%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.42-1.70 (4H, m), 1.82-1.94 (3H, m),2.27-2.29 (1H, m), 2.90-2.96 (1H, m), 4.64 (1H, dt, J=4.4, 10.3 Hz),6.84-6.86 (2H, m), 6.96 (1H, d, J=6.4 Hz), 7.09 (1H, dd, J=6.8, 11.2Hz), 7.64 (1H, dd, J=6.4, 10.3 Hz), 7.72 (1H, d, J=6.4 Hz), 8.18 (1H, d,J=6.4 Hz), 8.49 (1H, s).

MS (ESI) m/z: 462 [M+H]+.

Example 364-{[(1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(36a) 4-Cyclopent-1-en-1-ylpyridine-2-amine

The reaction and aftertreatment were conducted in the same manner as inExample 33a by using the 2-amino-4-chloropyridine (1.07 g, 8.32 mmol),2-cyclopent-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.61 g,8.29 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(303 mg,0.414 mmol), potassium carbonate (4.59 g, 33.2 mmol) and DMF (15 mL), toyield the title compound (552 mg, 41%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.00-2.04 (2H, m), 2.51-2.55 (2H, m),2.62-2.66 (2H, m), 4.39 (2H, brs), 6.34 (1H, t, J=2.0 Hz), 6.46 (1H, s),6.74 (1H, d, J=5.4 Hz), 7.99 (1H, d, J=5.4 Hz).

(36b) (1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the 4-cyclopent-1-en-1-ylpyridine-2-amine (552 mg,3.44 mmol) prepared in Example 36a, a borane-THF complex (0.95 M; 18.1mL, 17.2 mmol), sodium perborate tetrahydrate (531 mg, 3.44 mmol), THF(18 mL) and water (18 mL), to yield the title compound (110 mg, 18%) asa colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.50-1.59 (2H, m), 1.75-1.82 (2H, m),2.00-2.05 (2H, m), 2.83-2.90 (1H, m), 3.66-3.68 (1H, m), 4.47 (2H, brs),6.37 (1H, s), 6.54 (1H, d, J=6.4 Hz), 7.90 (1H, d, J=5.4 Hz).

(36c)4-{[(1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(285 mg, 0.649 mmol) prepared in Example 14b, the(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclopentanol (110 mg, 0.617 mmol)prepared in Example 36b, sodium hydride (63%; 35.3 mg, 0.927 mmol) andDMF (3.0 mL), to yield the title compound (185 mg, 50%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.70-1.79 (2H, m), 1.91-1.97 (2H, m),2.11-2.19 (1H, m), 2.24-2.30 (1H, m), 3.23 (1H, dt, J=4.9, 8.8 Hz), 3.76(3H, s), 3.79 (3H, s), 4.45 (2H, brs), 4.61-4.64 (1H, m), 5.23 (2H, s),6.35 (1H, s), 6.40-6.41 (2H, m), 6.49-6.52 (2H, m), 7.18-7.20 (2H, m),7.74 (1H, dd, J=6.4, 9.8 Hz), 8.00 (1H, d, J=5.4 Hz), 8.45 (1H, d, J=5.9Hz), 8.78 (1H, s).

(36d)4-{[(1S*,2R*)-2-(2-Aminopyridin-4-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(185 mg, 0.310 mmol) prepared in Example 36c, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (122 mg, 88%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.77-1.97 (4H, m), 2.25-2.37 (2H, m),3.35-3.40 (1H, m), 4.89-4.92 (1H, m), 6.84-6.86 (2H, m), 6.96-7.00 (2H,m), 7.74 (1H, dd, J=6.8, 10.3 Hz), 7.77 (1H, d, J=6.4 Hz), 8.23 (1H, d,J=6.4 Hz), 8.52 (1H, s).

MS (ESI) m/z: 448 [M+H]+.

Example 374-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(37a) (1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-ethylpyrazole (97%, 2.53 g, 25.5 mmol),N,N,N′,N′-tetramethylethylenediamine (3.83 mL, 25.5 mmol), butyl lithium(1.63 M solution in hexane; 18.3 mL, 29.8 mmol), cyclopentene oxide(2.66 g, 31.6 mmol) and THF (60 mL), to yield the title compound (750mg, 16%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.42 (3H, t, J=7.3 Hz), 1.63-1.91 (4H,m), 2.04-2.23 (2H, m), 3.02 (1H, q, J=8.3 Hz), 4.01-4.23 (3H, m), 6.01(1H, d, J=1.5 Hz), 7.41 (1H, s).

(37b)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(200 mg, 0.455 mmol) prepared in Example 14b,(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (78.0 mg, 0.432 mmol)prepared in Example 37a, sodium hydride (63%; 24.7 mg, 0.648 mmol) andDMF (2.0 mL), to yield the title compound (210 mg, 81%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.3 Hz), 1.75-1.97 (4H,m), 2.19-2.34 (2H, m), 3.47 (1H, dt, J=4.9, 8.3 Hz), 3.76 (3H, s), 3.79(3H, s), 4.11-4.23 (2H, m), 4.63-4.66 (1H, m), 5.23 (2H, s), 6.04 (1H,d, J=2.0 Hz), 6.39-6.42 (2H, m), 6.52 (1H, dd, J=6.4, 10.7 Hz),7.17-7.20 (2H, m), 7.43 (1H, d, J=2.0 Hz), 7.76 (1H, dd, J=6.4, 9.8 Hz),8.45 (1H, d, J=5.9 Hz), 8.77 (1H, s).

(37c)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(210 mg, 0.350 mmol) prepared in Example 37b, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (113 mg, 72%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.3 Hz), 1.75-1.83 (1H,m), 1.88-1.98 (3H, m), 2.19-2.34 (2H, m), 3.44-3.48 (1H, m), 4.10-4.24(2H, m), 4.63-4.66 (1H, m), 6.04 (1H, s), 6.58 (1H, dd, J=6.4, 10.7 Hz),7.25-7.27 (1H, m), 7.43 (1H, m), 7.74 (1H, dd, J=6.8, 10.3 Hz), 8.39(1H, d, J=5.9 Hz), 8.82 (1H, s).

MS (ESI) m/z: 450 [M+H]+.

Example 384-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(38a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(76.8 mg, 0.175 mmol) prepared in Example 30a, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (30.0 mg, 0.166 mmol)prepared in Example 37a, sodium hydride (63%; 9.5 mg, 0.249 mmol) andDMF (1.0 mL), to yield the title compound (80.0 mg, 80%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39 (3H, t, J=7.3 Hz), 1.74-1.83 (2H,m), 1.92-1.98 (2H, m), 2.22-2.35 (2H, m), 3.46 (1H, dt, J=4.9, 8.8 Hz),3.76 (3H, s), 3.79 (3H, s), 4.12-4.21 (2H, m), 4.74-4.76 (1H, m), 5.23(1H, d, J=16.6 Hz), 5.28 (1H, d, J=16.6. Hz), 6.05 (1H, d, J=1.5 Hz),6.39-6.42 (2H, m), 6.64 (1H, t, J=8.3 Hz), 7.19-7.20 (2H, m), 7.45 (1H,d, J=1.5 Hz), 7.70 (1H, dt, J=1.5, 7.3 Hz), 8.44 (1H, d, J=5.9 Hz), 8.76(1H, s).

(38b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(80.0 mg, 0.133 mmol) prepared in Example 38a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (30.0 mg, 50%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.3 Hz), 1.75-1.83 (1H,m), 1.93-1.96 (3H, m), 2.22-2.34 (2H, m), 3.46 (1H, dt, J=4.6, 8.3 Hz),4.10-4.22 (2H, m), 4.73-4.76 (1H, m), 6.05 (1H, d, J=1.5 Hz), 6.65 (1H,t, J=8.8 Hz), 7.20 (1H, d, J=6.4 Hz), 7.44 (1H, d, J=1.5 Hz), 7.68-7.72(1H, m), 8.35 (1H, d, J=6.4 Hz), 8.73 (1H, s).

MS (ESI) m/z: 450 [M+H]+.

Example 392,5-Difluoro-4-{[(1S*,2R*)-2-(pyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(39a) 3-Cyclohex-1-en-1-ylpyridine

A solution of 3-bromopyridine (0.38 g, 2.40 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g,2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12mmol) and cesium carbonate (1.72 g, 5.29 mmol) in 1,4-dioxane (8.0 mL)and water (4.0 mL) was stirred at 90° C. for 4 hours. After allowing tocool, the reaction solution was subjected to extraction with ethylacetate (50 mL), and the organic layer was dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withcolumn chromatography (hexane/ethyl acetate=2:1) to yield the titlecompound (347.3 mg, 99%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.65-1.83 (4H, m), 2.20-2.25 (2H, m),2.37-2.42 (2H, m), 6.16-6.18 (1H, m), 7.22 (1H, dd, J=4.7, 7.8 Hz), 7.64(1H, dt, J=2.0, 9.8 Hz), 8.45 (1H, dd, J=1.2, 6.3 Hz), 8.64 (1H, d,J=2.4 Hz).

(39b) (1S*,2R*)-2-(Pyridin-3-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the 3-cyclohex-1-en-1-ylpyridine (0.34 g, 2.14mmol) prepared in Example 39a, a borane-THF complex (0.95 M; 5.62 mL,5.34 mmol), sodium perborate tetrahydrate (0.85 g, 5.55 mmol), THF (2.1mL) and water (3.2 mL), to yield the title compound (0.12 g, 32%) as acolorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.32-1.56 (4H, m), 1.75-1.88 (3H, m),2.12-2.16 (1H, m), 2.43-2.49 (1H, m), 3.64-3.71 (1H, m), 7.22 (1H, dd,J=4.7, 7.8 Hz), 7.56 (1H, dt, J=2.0, 5.9 Hz), 8.37 (1H, dd, J=1.6, 4.7Hz), 8.44 (1H, d, J=2.4 Hz).

(39c)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(pyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.12 g, 0.27 mmol) prepared in Example 14b, the(1S*,2R*)-2-pyridin-3-ylcyclohexanol (0.05 g, 0.27 mmol) prepared inExample 39b, sodium hydride (63%; 0.02 g, 0.41 mmol) and DMF (1.4 mL),to yield the title compound (112.8 mg, 69%) as a colorless amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.42-1.74 (4H, m), 1.86-1.87 (1H, m),1.96-2.01 (2H, m), 2.25-2.28 (1H, m), 2.89-2.95 (1H, m), 3.76 (3H, s),3.78 (3H, s), 4.26 (1H, dt, J=4.3, 10.6 Hz), 5.18 (1H, d, J=17.6 Hz),5.22 (1H, d, J=17.6 Hz), 6.38-6.40 (2H, m), 6.49 (1H, dd, J=6.3, 11.3Hz), 7.15-7.18 (3H, m), 7.53 (1H, dt, J=2.0, 9.4 Hz), 7.62 (1H, dd,J=6.7, 9.8 Hz), 8.41 (1H, dd, J=1.2, 4.7 Hz), 8.44 (1H, d, J=5.9 Hz),8.53 (1H, d, J=2.4 Hz), 8.77 (1H, s).

(39d)2,5-Difluoro-4-{[(1S*,2R*)-2-(pyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-pyridin-3-ylcyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.11 g, 0.19 mmol) prepared in Example 39c, triethylsilane (0.15 mL),trifluoroacetic acid (0.19 g) and dichloromethane (1.9 mL), to yield thetitle compound (77 mg, 92%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.47-1.65 (3H, m), 1.77-1.94 (3H, m),2.00-2.04 (1H, m), 2.29-2.33 (1H, m), 3.10-3.16 (1H, m), 4.64 (1H, dt,J=3.9, 10.2 Hz), 6.99 (1H, dd, J=0.8, 6.3 Hz), 7.05 (1H, dd, J=6.7, 11.7Hz), 7.62 (1H, dd, J=6.7, 10.6 Hz), 7.73 (1H, dd, J=5.5, 8.2 Hz), 8.24(1H, dd, J=0.8, 6.7 Hz), 8.33 (1H, dt, J=1.6, 8.2 Hz), 6.53-8.54 (2H,m), 8.77 (1H, d, J=1.6 Hz).

MS (ESI) m/z: 447 [M+H]+.

Example 402,3-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(40a)N-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.40 g, 0.91 mmol) prepared in Example 30a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.16 g, 0.91 mmol)prepared in Example 4a, sodium hydride (63%; 0.050 g, 1.37 mmol) and DMF(4.6 mL), to yield the title compound (373 mg, 68%) as a colorlessamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.34-1.71 (4H, m), 1.86-1.97 (2H, m),2.04-2.08 (1H, m), 2.25-2.28 (1H, m), 2.98-3.04 (1H, m), 3.76 (3H, s),3.78 (3H, s), 3.90 (3H, s), 4.19-4.25 (1H, m), 5.20 (1H, d, J=16.8 Hz),5.25 (1H, d, J=17.2 Hz), 6.04 (1H, d, J=2.0 Hz), 6.38-6.41 (2H, m), 6.59(1H, t, J=8.6 Hz), 7.17-7.20 (2H, m), 7.34 (1H, d, J=1.6 Hz), 7.62-7.66(1H, m), 8.44 (1H, d, J=5.9 Hz), 8.76 (1H, s).

(40b)2,3-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.050 g, 0.09 mmol) prepared in Example 40a, triethylsilane (0.07 mL),trifluoroacetic acid (0.09 mL) and dichloromethane (0.9 mL), to yieldthe title compound (0.040 g, 86%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.45-1.61 (3H, m), 1.67-1.78 (1H, m),1.83-1.86 (1H, m), 1.91-1.93 (1H, m), 1.99-2.03 (1H, m), 2.27-2.30 (1H,m), 3.09-3.15 (1H, m), 3.86 (3H, s), 4.44-4.50 (1H, m), 6.14 (1H, d,J=2.0 Hz), 6.91-6.96 (1H, m), 7.02 (1H, d, J=6.3 Hz), 7.25 (1H, d, J=2.0Hz), 7.62-7.67 (1H, m), 8.25 (1H, d, J=6.3 Hz), 8.52 (1H, s).

MS (ESI) m/z: 450 [M+H]+.

Example 414-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(41a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.050 g, 0.11 mmol) prepared in Example 30a, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (0.020 g, 0.11 mmol)prepared in Example 12a, sodium hydride (63%; 0.010 g, 0.17 mmol) andDMF (0.6 mL), to yield the title compound (55.4 mg, 81%) as a colorlessamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.35-1.68 (4H, m), 1.42 (3H, t, J=7.4Hz), 1.86-1.89 (1H, m), 1.94-1.96 (1H, m), 2.03-2.07 (1H, m), 2.25-2.28(1H, m), 2.98-3.04 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 4.09-4.31 (3H,m), 5.19 (1H, d, J=16.8 Hz), 5.25 (1H, d, J=16.8 Hz), 6.02 (1H, d, J=2.0Hz), 6.39-6.41 (2H, m), 6.58-6.62 (1H, m), 7.17-7.20 (2H, m), 7.37 (1H,d, J=2.0 Hz), 7.62-7.66 (1H, m), 8.44 (1H, d, J=5.9 Hz), 8.76 (1H, d,J=1.2 Hz).

(41b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.060 g, 0.09 mmol) prepared in Example 41a, triethylsilane (0.07 mL),trifluoroacetic acid (0.09 mL) and dichloromethane (0.9 mL), to yieldthe title compound (34.9 mg, 82%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.36 (3H, t, J=7.4 Hz), 1.45-1.75 (4H,m), 1.82-1.85 (1H, m), 1.90-1.93 (1H, m), 1.97-2.02 (1H, m), 2.25-2.32(1H, m), 3.07-3.14 (1H, m), 4.11-4.19 (1H, m), 4.25-4.34 (1H, m),4.49-4.55 (1H, m), 6.14 (1H, d, J=2.0 Hz), 6.94-6.98 (1H, m), 7.02 (1H,d, J=6.3 Hz), 7.29 (1H, d, J=2.0 Hz), 7.63-7.68 (1H, m), 8.26 (1H, d,J=6.3 Hz), 8.53 (1H, s).

MS (ESI) m/z: 462 [M−H]−.

Example 422,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(42a)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(100 mg, 0.228 mmol) prepared in Example 14b, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (30 mg, 0.154 mmol)prepared in Example 9a, sodium hydride (63%; 40 mg, 1.05 mmol) and DMF(2 mL), to yield the title compound (50 mg, 53%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.57-1.99 (10H, m), 3.23 (1H, dt, J=3.4,9.8 Hz), 3.76 (3H, s), 3.78 (3H, s), 3.89 (3H, s), 4.34-4.38 (1H, m),5.19 (1H, d, J=16.6 Hz), 5.23 (1H, d, J=17.1 Hz), 6.00 (1H, d, J=2.0Hz), 6.39-6.42 (3H, m), 7.17-7.19 (2H, m), 7.33 (1H, d, J=2.0 Hz), 7.67(1H, dd, J=6.4, 9.8 Hz), 8.45 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(42b)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(50 mg, 0.0815 mmol) prepared in Example 42a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (32 mg, 85%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.61-1.98 (10H, m), 3.22 (1H, dt, J=2.9,9.3 Hz), 3.89 (3H, s), 4.32-4.36 (1H, m), 6.00 (1H, d, J=2.0 Hz), 6.45(1H, dd, J=6.4, 11.2 Hz), 7.21 (1H, brs), 7.32 (1H, d, J=2.0 Hz), 7.66(1H, dd, J=6.8, 9.8 Hz), 8.40 (1H, d, J=6.4 Hz), 8.78 (1H, s).

MS (ESI) m/z: 464 [M+H]+.

Example 432-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(43a)N-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.0g, 4.08 mmol) prepared in Example 14a,2,4-difluoro-5-methylbenzenesulfonyl chloride (WO 2010/079443; 1.85 g,8.15 mmol), 1,4-diazabicyclo[2.2.2]octane (0.91 g, 8.15 mmol) and THF(20 mL), to yield the title compound (1.41 g, 79%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.31 (3H, s), 3.77 (3H, s), 3.79 (3H, s),5.25 (2H, s), 6.40-6.42 (2H, m), 6.83 (1H, t, J=9.3 Hz), 7.20-7.23 (2H,m), 7.89 (1H, t, J=7.8 Hz), 8.45 (1H, d, J=5.9 Hz), 8.77 (1H, s).

(43b)N-(2,4-Dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.30 g, 0.69 mmol) prepared in Example 43a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.12 g, 0.72 mmol)prepared in Example 8a, sodium hydride (63%; 0.040 g, 1.05 mmol) and DMF(10 mL), to yield the title compound (0.20 g, 50%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.74-1.95 (4H, m), 2.16-2.34 (2H, m),2.20 (3H, s), 3.41 (1H, dt, J=4.9, 8.3 Hz), 3.76 (3H, s), 3.80 (3H, s),3.84 (3H, s), 4.62-4.65 (1H, m), 5.26 (2H, s), 6.04 (1H, d, J=2.0 Hz),6.37-6.42 (3H, m), 7.20 (1H, d, J=8.3 Hz), 7.26-7.28 (1H, m), 7.40 (1H,d, J=1.5 Hz), 7.76 (1H, d, J=7.8 Hz), 8.42 (1H, d, J=5.9 Hz), 8.76 (1H,s).

(43c)2-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.34 mmol) prepared in Example 43b, triethylsilane (0.10 mL),trifluoroacetic acid (0.50 mL) and dichloromethane (4.0 mL), to yieldthe title compound (0.16 g, 98%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.73-1.93 (4H, m), 2.18-2.34 (2H, m),2.21 (3H, s), 3.41 (1H, dt, J=4.4, 7.8 Hz), 3.84 (3H, s), 4.62-4.65 (1H,m), 6.04 (1H, d, J=1.5 Hz), 6.44 (1H, d, J=11.7 Hz), 7.24-7.25 (1H, m),7.39 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=7.8 Hz), 8.41 (1H, d, J=5.9 Hz),8.86 (1H, brs).

MS (ESI) m/z: 432 [M+H]+.

Example 442-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(44a)N-(2,4-Dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.40 g, 0.95 mmol) prepared in Example 29a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.17 g, 0.95 mmol)prepared in Example 4a, sodium hydride (63%; 0.040 g, 1.14 mmol) and DMF(4.8 mL), to yield the title compound (489 mg, 89%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.25-1.63 (4H, m), 1.86-1.88 (1H, m),1.93-1.95 (1H, m), 2.03-2.06 (1H, m), 2.24-2.26 (1H, m), 2.91-2.96 (1H,m), 3.77 (3H, s), 3.79 (3H, s), 3.88 (3H, s), 4.13-4.18 (1H, m), 5.23(2H, s), 5.99 (1H, d, J=2.0 Hz), 6.39-6.44 (3H, m), 6.58 (1H, dd, J=2.0,8.8 Hz), 7.20 (2H, dd, J=8.3, 11.2 Hz), 7.34 (1H, d, J=2.0 Hz), 7.86(1H, t, J=8.3 Hz), 8.42 (1H, d, J=5.9 Hz), 8.75 (1H, s).

(44b)2-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.49 g, 0.84 mmol) prepared in Example 44a, triethylsilane (0.67 mL),trifluoroacetic acid (0.84 mL) and dichloromethane (8.4 mL), to yieldthe title compound (318 mg, 88%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.25-1.74 (4H, m), 1.81-1.90 (2H, m),1.97-2.02 (1H, m), 2.21-2.24 (1H, m), 3.02-3.08 (1H, m), 3.84 (3H, s),4.42 (1H, dt, J=3.9, 10.2 Hz), 6.12 (1H, d, J=2.4 Hz), 6.69 (1H, dd,J=2.4, 12.5 Hz), 6.74 (1H, dd, J=2.7, 9.0 Hz), 7.03 (1H, dd, J=1.2, 6.3Hz), 7.24 (1H, d, J=1.6 Hz), 7.84 (1H, t, J=8.6 Hz), 8.30 (1H, d, J=6.3Hz), 8.85 (1H, d, J=2.0 Hz).

MS (ESI) m/z: 432 [M+H]+.

Example 454-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(45a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.40 g, 0.95 mmol) prepared in Example 29a, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (0.18 g, 0.95 mmol)prepared in Example 12a, sodium hydride (63%; 0.040 g, 1.14 mmol) andDMF (4.8 mL), to yield the title compound (506.4 mg, 90%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.36-1.50 (3H, m), 1.44 (3H, t, J=6.8Hz), 1.57-1.62 (1H, m), 1.85-1.88 (1H, m), 1.93-1.94 (1H, m), 2.02-2.05(1H, m), 2.22-2.28 (1H, m), 2.91-2.96 (1H, m), 3.76 (3H, s), 3.79 (3H,s), 4.10-4.28 (3H, m), 5.23 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.39-6.44(3H, m), 6.58 (1H, dd, J=2.4, 8.8 Hz), 7.21 (2H, dd, J=8.3, 13.2 Hz),7.36 (1H, d, J=2.0 Hz), 7.86 (1H, t, J=8.3 Hz), 8.42 (1H, d, J=5.9 Hz),8.75 (1H, s).

(45b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.51 g, 0.85 mmol) prepared in Example 45a, triethylsilane (0.68 mL),trifluoroacetic acid (0.85 mL) and dichloromethane (8.5 mL), to yieldthe title compound (333.4 mg, 88%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.29-1.73 (4H, m), 1.37 (3H, t, J=7.4Hz), 1.81-1.90 (2H, m), 1.97-2.01 (1H, m), 2.22-2.26 (1H, m), 3.00-3.07(1H, m), 4.07-4.18 (1H, m), 4.23-4.31 (1H, m), 4.46 (1H, dt, J=3.9, 10.2Hz), 6.12 (1H, d, J=2.0 Hz), 6.67 (1H, dd, J=2.4, 12.5 Hz), 6.73 (1H,dd, J=2.4, 9.0 Hz), 7.04 (1H, dd, J=1.2, 6.3 Hz), 7.28 (1H, d, J=2.4Hz), 7.84 (1H, t, J=8.6 Hz), 8.30 (1H, d, J=6.3 Hz), 8.55 (1H, s).

MS (ESI) m/z: 446 [M+H]+.

Example 462,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(46a)N-(2,4-Dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.19 g, 0.43 mmol) prepared in Example 27a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.080 g, 0.45 mmol)prepared in Example 4a, sodium hydride (63%; 0.030 g, 0.79 mmol) and DMF(5 mL), to yield the title compound (0.12 g, 48%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-1.67 (4H, m), 1.86-1.88 (1H, m),1.94-1.95 (1H, m), 2.03-2.06 (1H, m), 2.22-2.24 (1H, m), 2.90-2.95 (1H,m), 3.77 (3H, s), 3.81 (3H, s), 3.86 (3H, s), 4.10-4.15 (1H, m), 5.24(2H, s), 5.99 (1H, d, J=2.0 Hz), 6.29 (2H, d, J=10.7 Hz), 6.40-6.44 (2H,m), 7.14 (1H, dd, J=1.0, 5.9 Hz), 7.21 (1H, d, J=8.3 Hz), 7.34 (1H, d,J=2.0 Hz), 8.44 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(46b)2,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.12 g, 0.21 mmol) prepared in Example 46a, triethylsilane (0.10 mL),trifluoroacetic acid (0.50 mL) and dichloromethane (2.0 mL), to yieldthe title compound (0.030 g, 30%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.38-1.65 (4H, m), 1.85-1.88 (1H, m),1.93-1.95 (1H, m), 2.03-2.08 (1H, m), 2.22-2.24 (1H, m), 2.89-2.96 (1H,m), 3.86 (3H, s), 4.09-4.15 (1H, m), 6.00 (1H, d, J=2.0 Hz), 6.32 (2H,d, J=10.6 Hz), 7.34 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=6.7 Hz), 8.41 (1H,d, J=6.3 Hz), 8.80 (1H, s).

MS (ESI) m/z: 450 [M+H]+.

Example 474-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(47a) 5-(4,4-Difluorocyclohex-1-en-1-yl)-1-methyl-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using 5-iodo-1-methyl-1H-pyrazole (1.90 g, 9.14 mmol),2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.00 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium (0) (240 mg,0.208 mmol), cesium carbonate (2.70 g, 8.29 mmol), 1,4-dioxane (10 mL)and water (5 mL), to yield the title compound (767 mg, 94%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.13-2.22 (2H, m), 2.56-2.60 (2H, m),2.73 (2H, t, J=14.2 Hz), 3.86 (3H, s), 5.73 (1H, brs), 6.14 (1H, d,J=2.0 Hz), 7.42 (1H, d, J=2.0 Hz).

(47b) (1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the5-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-pyrazole (767 mg, 3.87mmol) prepared in Example 47a, a borane-THF complex (0.95 M; 12.2 mL,11.6 mmol), sodium perborate tetrahydrate (1.20 g, 7.80 mmol), THF (4.0mL) and water (8.0 mL), to yield the title compound (148 mg, 18%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.68-1.95 (4H, m), 2.16-2.21 (1H, m),2.51-2.57 (1H, m), 2.61-2.66 (1H, m), 3.76-3.83 (1H, m), 3.80 (3H, s),3.89 (1H, brs), 6.02 (1H, d, J=2.0 Hz), 7.26 (1H, d, J=1.5 Hz).

(47c)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(160 mg, 0.364 mmol) prepared in Example 14b, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (76 mg,0.351 mmol) prepared in Example 47b, sodium hydride (63%; 40 mg, 1.05mmol) and DMF (2.0 mL), to yield the title compound (212 mg, 92%) as acolorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.92-2.12 (4H, m), 2.29-2.33 (1H, m),2.71-2.77 (1H, m), 3.07-3.12 (1H, m), 3.77 (3H, s), 3.78 (3H, s), 3.92(3H, s), 4.32 (1H, dt, J=4.9, 10.7 Hz), 5.19 (1H, d, J=17.1 Hz), 5.23(1H, d, J=17.1 Hz), 6.07 (1H, d, J=2.0 Hz), 6.39-6.44 (3H, m), 7.15-7.19(2H, m), 7.36 (1H, d, J=2.0 Hz), 7.71 (1H, dd, J=6.4, 9.8 Hz), 8.46 (1H,d, J=5.9 Hz), 8.78 (1H, s).

(47d)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(212 mg, 0.334 mmol) prepared in Example 47c, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (153 mg, 95%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.36-1.77 (1H, m), 1.96-2.28 (4H, m),2.64-2.71 (1H, m), 3.35-3.40 (1H, m), 3.79 (3H, s), 4.71 (1H, dt, J=4.4,10.7 Hz), 6.19 (1H, d, J=1.5 Hz), 6.94 (1H, brs), 7.12-7.16 (1H, m),7.18 (1H, d, J=2.0 Hz), 7.61-7.64 (1H, m), 8.24 (1H, brs), 8.56 (1H, s).

MS (ESI) m/z: 486 [M+H]+.

Example 485-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(48a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.234 g, 0.513 mmol) prepared in Example 20a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.116 g, 0.644 mmol)prepared in Example 4a, sodium hydride (63%; 0.023 g, 0.600 mmol) andDMF (2 mL), to yield the title compound (0.273 g, 86%) as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-1.68 (4H, m), 1.85-1.97 (2H, m),2.04-2.10 (1H, m), 2.18-2.23 (1H, m), 3.02-3.09 (1H, m), 3.76 (3H, s),3.76 (3H, s), 3.93 (3H, s), 4.09-4.17 (1H, m), 5.21 (2H, s), 6.03 (1H,d, J=2.0 Hz), 6.38-6.45 (3H, m), 7.17-7.22 (2H, m), 7.35 (1H, d, J=2.0Hz), 7.92 (1H, d, J=7.4 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, d, J=1.2Hz).

(48b)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.27 g, 0.438 mmol) prepared in Example 48a, triethylsilane (0.168 mL,1.05 mmol), trifluoroacetic acid (3.4 mL) and dichloromethane (3.4 mL),to yield the title compound (0.148 g, 72%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.36-1.70 (4H, m), 1.85-1.96 (2H, m),2.03-2.11 (1H, m), 2.18-2.23 (1H, m), 3.01-3.09 (1H, m), 3.93 (3H, s),4.09-4.17 (1H, m), 6.03 (1H, d, J=2.0 Hz), 6.47 (1H, d, J=11.7 Hz),7.23-7.27 (1H, m), 7.34 (1H, d, J=2.0 Hz), 7.94 (1H, d, J=7.8 Hz), 8.39(1H, d, J=6.3 Hz), 8.81 (1H, s).

MS (ESI) m/z: 466 [M+H]+.

Example 492,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-imidazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(49a) 2-(1-Methyl-1H-imidazol-5-yl)cyclohex-2-en-1-one

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using (6-oxocyclohex-1-en-1-yl)boric acid (J. Org. Chem.2011, 76, 3946-3959; 790 mg, 5.65 mmol), 5-bromo-1-methyl-1H-imidazole(910 mg, 5.65 mmol), tetrakis(triphenylphosphine)palladium (0) (326 mg,0.282 mmol), cesium carbonate (4.00 g, 12.3 mmol), 1,4-dioxane (10 mL)and water (5 mL), to yield the title compound (80 mg, 8%) as a brownoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.10-2.17 (2H, m), 2.54-2.60 (4H, m),3.46 (3H, s), 6.92 (1H, d, J=1.0 Hz), 7.10 (1H, t, J=4.4 Hz), 7.44 (1H,s).

(49b) 2-(1-Methyl-1H-imidazol-5-yl)cyclohexanol

To a solution of the 2-(1-methyl-1H-imidazol-5-yl)cyclohex-2-en-1-one(80 mg, 0.454 mmol) prepared in Example 49a in methanol (2.0 mL), sodiumborohydride (50 mg, 1.32 mmol) was added at room temperature, and thereaction solution was stirred at room temperature for 30 minutes. To thereaction solution, a saturated aqueous solution of ammonium chloride (20mL) was added, followed by extraction with dichloromethane (50 mL). Thethus obtained organic layer was dried over anhydrous sodium sulfate andvacuum concentrated to yield the title compound (50 mg, 61%) in the formof a trans/cis (2:1) mixture as a colorless oil.

(49c)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-imidazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(120 mg, 0.273 mmol) prepared in Example 14b,2-(1-methyl-1H-imidazol-5-yl)cyclohexanol (50 mg, 0.277 mmol) preparedin Example 49b, sodium hydride (63%; 40 mg, 1.05 mmol) and DMF (2.0 mL),to yield the title compound (46 mg, 28%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-1.53 (3H, m), 1.68-1.77 (1H, m),1.88-1.95 (2H, m), 2.06-2.24 (2H, m), 2.85-2.90 (1H, m), 3.66 (3H, s),3.77 (3H, s), 3.78 (3H, s), 4.03-4.08 (1H, m), 5.19 (1H, d, J=16.6 Hz),5.24 (1H, d, J=16.6 Hz), 6.39-6.41 (2H, m), 6.47 (1H, dd, J=6.4, 11.2Hz), 6.85 (1H, s), 7.16-7.20 (2H, m), 7.29 (1H, s), 7.68 (1H, dd, J=6.4,9.8 Hz), 8.45 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(49d)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-imidazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-imidazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(46 mg, 0.0767 mmol) prepared in Example 49c, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL), to yield thetitle compound (33 mg, 96%) as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.34-1.83 (6H, m), 1.95-1.99 (1H, m),2.19-2.22 (1H, m), 3.11-3.16 (1H, m), 3.84 (3H, s), 4.49 (1H, dt, J=3.5,10.2 Hz), 6.94 (1H, d, J=6.3 Hz), 7.32 (1H, dd, J=3.1, 11.7 Hz), 7.45(1H, s), 7.65 (1H, dd, J=6.7, 10.6 Hz), 8.23 (1H, d, J=6.6 Hz), 8.56(1H, s), 8.71 (1H, brs).

MS (ESI) m/z: 448 [M−H]−.

Example 504-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(50a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(311 mg, 0.703 mmol) prepared in Example 27a, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (127 mg, 0.703 mmol)prepared in Example 37a, sodium hydride (63%; 35.1 mg, 0.921 mmol) andDMF (5.0 mL), to yield the title compound (231 mg, 55%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.3 Hz), 1.73-1.95 (4H,m), 2.18-2.31 (2H, m), 3.36 (1H, dt, J=4.9, 8.3 Hz), 3.77 (3H, s), 3.82(3H, s), 4.09-4.15 (2H, m), 4.62-4.65 (1H, m), 5.26 (2H, s), 6.03 (1H,d, J=2.0 Hz), 6.37-6.44 (4H, m), 7.16 (1H, dd, J=1.0, 5.9 Hz), 7.22 (1H,d, J=8.3 Hz), 7.44 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=5.9 Hz), 8.78 (1H,s).

(50b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(231 mg, 0.385 mmol) prepared in Example 50a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (151 mg, 87%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.3 Hz), 1.71-1.77 (1H,m), 1.84-1.95 (3H, m), 2.17-2.32 (2H, m), 3.37 (1H, dt, J=4.9, 8.3 Hz),4.09-4.18 (2H, m), 4.61-4.64 (1H, m), 6.02 (1H, d, J=2.0 Hz), 6.41 (2H,d, J=10.7 Hz), 7.40 (1H, d, J=5.9 Hz), 7.43 (1H, d, J=2.0 Hz), 8.42 (1H,d, J=6.4 Hz), 8.86 (1H, s).

MS (ESI) m/z: 450 [M+H]+.

Example 512,3-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(51a)N-(2,4-Dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(201 mg, 0.457 mmol) prepared in Example 30a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (84.5 mg, 0.585mmol) prepared in Example 9a, sodium hydride (63%; 24.9 mg, 0.654 mmol)and DMF (3.0 mL), to yield the title compound (190 mg, 72%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.60-2.00 (10H, m), 3.23 (1H, dt, J=2.9,9.3 Hz), 3.77 (3H, s), 3.78 (3H, s), 3.89 (3H, s), 4.45-4.49 (1H, m),5.20 (1H, d, J=17.1 Hz), 5.25 (1H, d, J=16.6 Hz), 6.02 (1H, d, J=2.0Hz), 6.40-6.41 (2H, m), 6.53 (1H, t, J=8.3 Hz), 7.19 (2H, d, J=8.3 Hz),7.33 (1H, d, J=1.5 Hz), 7.66 (1H, t, J=9.3 Hz), 8.44 (1H, d, J=5.9 Hz),8.76 (1H, s).

(51b)2,3-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(190 mg, 0.310 mmol) prepared in Example 51a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (102 mg, 71%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.59-2.00 (10H, m), 3.23 (1H, dt, J=2.9,9.3 Hz), 3.88 (3H, s), 4.44-4.48 (1H, m), 6.03 (1H, s), 6.55 (1H, t,J=7.3 Hz), 7.27 (1H, d, J=6.4 Hz), 7.34 (1H, brs), 7.65 (1H, t, J=7.3Hz), 8.35 (1H, d, J=6.4 Hz), 8.83 (1H, s).

MS (ESI) m/z: 464 [M+H]+.

Example 523-Methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(52a)N-(2,4-dimethoxybenzyl)-4-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (590mg, 2.40 mmol) prepared in Example 14a, 4-fluoro-3-methylbenzenesulfonylchloride (WO 2010/079443; 1000 mg, 4.79 mmol),1,4-diazabicyclo[2.2.2]octane (537 mg, 4.79 mmol) and THF (20 mL), toyield the title compound (598 mg, 50%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.28 (3H, s), 3.73 (3H, s), 3.78 (3H, s),5.22 (2H, s), 6.39-6.41 (2H, m), 7.08 (1H, t, J=8.8 Hz), 7.14 (1H, d,J=7.8 Hz), 7.26-7.29 (1H, m), 7.64 (1H, dd, J=2.0, 6.8 Hz), 7.70-7.73(1H, m), 8.48 (1H, d, J=5.9 Hz), 8.83 (1H, s).

(52b)N-(2,4-Dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-4-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(500 mg, 1.20 mmol) prepared in Example 52a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (209 mg, 1.26 mmol)prepared in Example 8a, sodium hydride (60%; 71.9 mg, 1.80 mmol) and DMF(15 mL), to yield the title compound (356 mg, 53%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.62-1.96 (4H, m), 2.18-2.32 (2H, m),2.18 (3H, s), 3.40 (1H, dt, J=4.9, 8.3 Hz), 3.75 (3H, s), 3.76 (3H, s),3.82 (3H, s), 4.71-4.74 (1H, m), 5.23 (2H, s), 6.05 (1H, d, J=2.0 Hz),6.39 (1H, dd, J=2.4, 10.7 Hz), 6.42 (1H, d, J=2.0 Hz), 6.66 (1H, d,J=8.8 Hz), 7.13 (1H, d, J=8.8 Hz), 7.33 (1H, dd, J=1.0, 5.9 Hz),7.37-7.39 (1H, m), 7.53 (1H, dd, J=1.0, 2.4 Hz), 7.65 (1H, dd, J=2.4,8.8 Hz), 8.42 (1H, d, J=6.4 Hz), 8.78 (1H, s).

(52c)3-Methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(356 mg, 0.632 mmol) prepared in Example 52b, triethylsilane (0.20 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (202 mg, 68%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.75-1.93 (4H, m), 2.17-2.32 (2H, m),2.22 (3H, s), 3.40 (1H, dt, J=4.0, 7.8 Hz), 3.81 (3H, s), 4.71-4.74 (1H,m), 6.05 (1H, d, J=2.0 Hz), 6.69 (1H, d, J=8.8 Hz), 7.23 (1H, d, J=4.4Hz), 7.40 (1H, d, J=2.0 Hz), 7.69-7.73 (2H, m), 8.46 (1H, d, J=5.9 Hz),8.81 (1H, s).

MS (ESI) m/z: 413 [M+H]+.

Example 532,5-Difluoro-4-{[(1S*,2R*)-2-(pyridazin-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(53a) 4-Cyclohex-1-en-1-ylpyridazine

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using 4-bromopyridazine hydrobromide (0.50 g, 2.09 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.43 g,2.09 mmol), tetrakis(triphenylphosphine)palladium (0) (0.12 g, 0.10mmol), cesium carbonate (1.50 g, 4.59 mmol), 1,4-dioxane (7.0 mL) andwater (3.5 mL), to yield the title compound (301 mg, 99%) as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.67-1.85 (4H, m), 2.27-2.30 (2H, m),2.36-2.40 (2H, m), 6.54-6.56 (1H, m), 7.35 (1H, dd, J=2.4, 5.5 Hz), 9.07(1H, dd, J=1.2, 5.5 Hz), 9.25 (1H, dd, J=1.2, 2.7 Hz).

(53b) (1S*,2R*)-2-Pyridazin-4-ylcyclohexanol

To a solution of the 4-(cyclohex-1-en-1-yl)pyridazine (0.15 g, 0.94mmol) prepared in Example 53a in dichloromethane (9.4 mL),3-chloroperbenzoic acid (0.76 g, 3.09 mmol) was added with cooling onice, and the reaction solution was stirred at room temperature for 4hours. A highly polar compound was removed with a silica gel pad(dichloromethane) to yield crude epoxide. A solution of the crudeepoxide and Raney nickel in ethanol (3.0 mL) was stirred at 70° C. for 3hours under a hydrogen atmosphere. The reaction solution was filtered,and the residue was then purified with silica gel chromatography toyield the title compound (35 mg, 31%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.31-1.55 (4H, m), 1.80-1.90 (3H, m),2.15-2.17 (1H, m), 2.46-2.52 (1H, m), 3.71 (1H, dt, J=4.4, 10.3 Hz),7.35 (1H, dd, J=2.4, 5.4 Hz), 8.96 (1H, d, J=5.4 Hz), 9.01 (1H, s).

(53c)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(pyridazin-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.04 g, 0.08 mmol) prepared in Example 14b, the(1S*,2R*)-2-pyridazin-4-ylcyclohexanol (0.01 g, 0.08 mmol) prepared inExample 53b, sodium hydride (63%; 5 mg, 0.12 mmol) and DMF (0.40 mL), toyield the title compound (44 mg, 93%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.46-1.70 (4H, m), 1.90-1.92 (1H, m),1.96-2.05 (2H, m), 2.28-2.31 (1H, m), 2.91-2.97 (1H, m), 3.76 (3H, s),3.77 (3H, s), 4.28 (1H, dt, J=4.4, 10.3 Hz), 5.18 (1H, d, J=17.1 Hz),5.22 (1H, d, J=17.1 Hz), 6.38-6.42 (2H, m), 6.57 (1H, dd, J=6.4, 11.2Hz), 7.17-7.18 (2H, m), 7.35 (1H, dd, J=2.0, 5.4 Hz), 7.66 (1H, dd,J=6.8, 10.3 Hz), 8.45 (1H, d, J=5.9 Hz), 8.77 (1H, s), 9.08 (1H, d,J=5.4 Hz), 9.15 (1H, s).

(53d)2,5-Difluoro-4-{[(1S*,2R*)-2-(pyridazin-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(pyridazin-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.04 g, 0.07 mmol) prepared in Example 53c, triethylsilane (0.06 mL),trifluoroacetic acid (0.07 mL) and dichloromethane (0.74 mL), to yieldthe title compound (30 mg, 94%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.36-1.63 (4H, m), 1.74-1.88 (3H, m),2.20-2.23 (1H, m), 2.94-2.98 (1H, m), 4.86 (1H, dt, J=3.9, 10.7 Hz),6.84-7.03 (1H, m), 7.33 (1H, brs), 7.56 (1H, brs), 7.61 (1H, dd, J=2.4,5.4 Hz), 8.23 (1H, brs), 8.55 (1H, s), 9.06 (1H, d, J=5.4 Hz), 9.21 (1H,s).

MS (ESI) m/z: 448 [M+H]+.

Example 543-Methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(54a)N-(2,4-Dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-4-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.25 g, 0.60 mmol) prepared in Example 52a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.11 g, 0.63 mmol)prepared in Example 4a, sodium hydride (63%; 0.040 g, 0.90 mmol) and DMF(10 mL), to yield the title compound (79 mg, 23%) as a colorlessamorphous solid.

(54b)3-Methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(79 mg, 0.14 mmol) prepared in Example 54a, triethylsilane (0.1 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (49 mg, 84%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-1.65 (4H, m), 1.85-1.93 (2H, m),2.05 (3H, s), 2.05-2.07 (1H, m), 2.24-2.29 (1H, m), 3.00 (1H, dt, J=3.4,9.8 Hz), 3.88 (3H, s), 4.21-4.26 (1H, m), 5.98 (1H, d, J=2.0 Hz), 6.71(1H, d, J=8.8 Hz), 7.21 (1H, brs), 7.33 (1H, s), 7.62 (1H, brs), 7.67(1H, d, J=8.3 Hz), 8.47 (1H, d, J=5.9 Hz), 8.84 (1H, s).

MS (ESI) m/z: 427 [M+H]+.

Example 553-Cyano-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(55a)3-Cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(198 mg, 0.46 mmol) prepared in Example 26a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (94.1 mg, 0.48 mmol)prepared in Example 9a, sodium hydride (60%; 27.7 mg, 0.69 mmol) and DMF(10 mL), to yield the title compound (195 mg, 70%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.58-1.72 (3H, m), 1.75-1.95 (5H, m),1.97-2.02 (1H, m), 1.99 (1H, d, J=4.7 Hz), 3.30 (1H, dt, J=2.4, 9.0 Hz),3.62 (3H, s), 3.79 (3H, s), 3.94 (3H, s), 4.58 (1H, dd, J=5.5, 9.4 Hz),5.11 (1H, d, J=16.8 Hz), 5.16 (1H, d, J=16.8 Hz), 6.02 (1H, d, J=2.0Hz), 6.41 (1H, dd, J=2.4, 8.2 Hz), 6.35 (1H, d, J=2.4 Hz), 6.74 (1H, d,J=9.4 Hz), 7.12 (1H, d, J=6.3 Hz), 7.11 (1H, d, J=4.3 Hz), 7.32 (1H, s),7.87 (1H, d, J=2.4 Hz), 8.00 (1H, dd, J=2.4, 9.0 Hz), 8.50 (1H, d, J=5.9Hz), 8.85 (1H, s).

(55b)3-Cyano-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(195 mg, 0.32 mmol) prepared in Example 55a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (102 mg, 70%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.55-1.74 (3H, m), 1.76-1.95 (5H, m),1.96-2.14 (2H, m), 3.30 (1H, dt, J=2.7, 9.2 Hz), 3.94 (3H, s), 4.58 (1H,dd, J=6.4, 13.2 Hz), 6.02 (1H, d, J=2.0 Hz), 6.81 (1H, d, J=9.3 Hz),7.16 (1H, d, J=5.9 Hz), 7.32 (1H, d, J=2.0 Hz), 7.98 (1H, dd, J=2.4, 8.8Hz), 8.07 (1H, s), 8.41 (1H, d, J=6.4 Hz), 8.78 (1H, brs).

MS (ESI) m/z: 452 [M+H]+.

Example 563-Cyano-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(56a)3-Cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.466 mmol) prepared in Example 26a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.084 g, 0.466 mmol)prepared in Example 4a, sodium hydride (63%; 0.027 g, 0.699 mmol) andDMF (3.0 mL), to yield the title compound (0.090 g, 34%) as a colorlessamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.36-1.68 (4H, m), 1.87-1.90 (1H, m),1.97-1.99 (1H, m), 2.05-2.10 (1H, m), 2.20-2.24 (1H, m), 3.04-3.11 (1H,m), 3.63 (3H, s), 3.79 (3H, s), 3.95 (3H, s), 4.34 (1H, dt, J=3.9, 10.2Hz), 5.10 (1H, d, J=16.8 Hz), 5.15 (1H, d, J=16.0 Hz), 6.04 (1H, d,J=1.6 Hz), 6.36 (1H, d, J=2.4 Hz), 6.41 (1H, dd, J=2.4, 8.2 Hz), 6.79(1H, d, J=9.0 Hz), 7.09-7.13 (2H, m), 7.34 (1H, d, J=1.6 Hz), 7.85 (1H,d, J=2.4 Hz), 7.98 (1H, dd, J=2.4, 9.0 Hz), 8.50 (1H, d, J=5.9 Hz), 8.84(1H, d, J=0.8 Hz).

(56b)3-Cyano-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.090 g, 0.15 mmol) prepared in Example 56a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (43 mg, 64%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.38-1.63 (4H, m), 1.72-1.74 (1H, m),1.80-1.82 (1H, m), 1.90-1.93 (1H, m), 2.16-2.18 (1H, m), 3.11-3.16 (1H,m), 3.84 (3H, s), 4.67 (1H, t, J=3.9, 9.8 Hz), 6.07 (1H, d, J=2.0 Hz),6.93 (1H, brs), 7.17 (1H, d, J=1.5 Hz), 7.38 (1H, d, J=9.3 Hz), 8.00(1H, dd, J=2.0, 9.3 Hz), 8.10 (1H, s), 8.25 (1H, brs), 8.60 (1H, s).

MS (ESI) m/z: 439 [M+H]+.

Example 573-Methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(57a)N-(2,4-Dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-4-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(258 mg, 0.62 mmol) prepared in Example 52a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (120 mg, 0.62 mmol)prepared in Example 9a, sodium hydride (63%; 35.3 mg, 2.33 mmol) and DMF(10 mL), to yield the title compound (182 mg, 50%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.61-1.99 (10H, m), 2.01 (3H, s), 3.21(1H, dt, J=3.5, 9.0 Hz), 3.73 (3H, s), 3.77 (3H, s), 3.86 (3H, s),4.47-4.51 (1H, m), 5.22 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.37-6.40 (2H,m), 6.61 (1H, d, J=9.0 Hz), 7.13 (1H, d, J=8.2 Hz), 7.32-7.34 (2H, m),7.45 (1H, s), 7.63 (1H, dd, J=2.0, 9.0 Hz), 8.44 (1H, d, J=5.9 Hz), 8.80(1H, s).

(57b)3-Methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(182 mg, 0.31 mmol) prepared in Example 57a, triethylsilane (0.15 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (100 mg, 74%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) 5 ppm: 1.58-2.04 (10H, m), 2.04 (3H, s),3.19-3.23 (1H, m), 3.87 (3H, s), 4.47-4.51 (1H, m), 5.98 (1H, s), 6.64(1H, d, J=8.8 Hz), 7.26-7.33 (2H, m), 7.61 (1H, s), 7.68 (1H, dd, J=2.4,8.8 Hz), 8.49 (1H, brs), 8.97 (1H, brs).

MS (ESI) m/z: 442 [M+H]+.

Example 582-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(58a)N-(2,4-Dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.30 g, 0.71 mmol) prepared in Example 29a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (0.14 g, 0.71 mmol)prepared in Example 9a, sodium hydride (63%; 0.040 g, 1.07 mmol) and DMF(3.6 mL), to yield the title compound (260.2 mg, 61%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.25-1.38 (4H, m), 1.60-1.98 (6H, m),3.16 (1H, dt, J=2.9, 8.8 Hz), 3.76 (3H, s), 3.79 (3H, s), 3.86 (3H, s),4.39-4.43 (1H, m), 5.24 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.39-6.41 (3H,m), 6.55 (1H, dd, J=2.0, 8.8 Hz), 7.19 (1H, d, J=8.3 Hz), 7.23 (1H, dd,J=1.0, 5.9 Hz), 7.33 (1H, d, J=1.5 Hz), 7.88 (1H, t, J=8.3 Hz), 8.42(1H, d, J=5.9 Hz), 8.76 (1H, s).

(58b)2-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.26 g, 0.44 mmol) prepared in Example 58a, triethylsilane (0.35 mL),trifluoroacetic acid (0.44 mL) and dichloromethane (4.4 mL), to yieldthe title compound (0.15 g, 77%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.51-1.92 (10H, m), 3.20-3.23 (1H, m),3.77 (3H, s), 4.69-4.73 (1H, m), 6.08 (1H, d, J=2.0 Hz), 6.77 (1H, d,J=9.3 Hz), 6.87 (1H, d, J=11.7 Hz), 6.99 (1H, brs), 7.17 (1H, d, J=1.5Hz), 7.76 (1H, t, J=5.9 Hz), 8.31 (1H, brs), 8.56 (1H, s).

MS (ESI) m/z: 446 [M+H]+.

Example 594-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(59a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.45 mmol) prepared in Example 27a, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (0.088 g, 0.45 mmol)prepared in Example 12a, sodium hydride (63%; 0.027 g, 0.67 mmol) andDMF (3.0 mL), to yield the title compound (0.085 g, 55%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.64 (4H, m), 1.44 (3H, t, J=7.3Hz), 1.86-1.88 (1H, m), 1.94-1.95 (1H, m), 2.02-2.05 (1H, m), 2.23-2.26(1H, m), 2.90-2.95 (1H, m), 3.77 (3H, s), 3.81 (3H, s), 4.01-4.25 (3H,m), 5.24 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.29 (2H, d, J=10.7 Hz), 6.41(1H, dd, J=2.4, 10.7 Hz), 6.43-6.44 (1H, m), 7.16 (1H, d, J=7.3 Hz),7.21 (1H, d, J=8.3 Hz), 8.38 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=5.9 Hz),8.78 (1H, s).

(59b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.080 g, 0.13 mmol) prepared in Example 59a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (25 mg, 42%) as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.24-1.56 (4H, m), 1.29 (3H, t, J=7.0Hz), 1.69-1.79 (2H, m), 1.86-1.89 (1H, m), 2.10-2.13 (1H, m), 2.97-3.04(1H, m), 4.03-4.16 (2H, m), 4.57 (1H, dt, J=3.5, 9.8 Hz), 6.06 (1H, s),6.73 (2H, d, J=11.7 Hz), 6.92 (1H, brs), 7.22 (1H, s), 8.29 (1H, brs),8.58 (1H, s).

MS (ESI) m/z: 464 [M+H]+.

Example 605-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(60a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(300 mg, 0.66 mmol) prepared in Example 20a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (134 mg, 0.69 mmol)prepared in Example 9a, sodium hydride (60%; 39.5 mg, 0.99 mmol) and DMF(10 mL), to yield the title compound (202 mg, 49%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.55-1.71 (1H, m), 1.61 (3H, dd, J=4.4,8.8 Hz), 1.77-1.86 (2H, m), 1.87-1.98 (4H, m), 3.27 (1H, t, J=9.3 Hz),3.76 (6H, s), 3.91 (3H, s), 4.40 (1H, dd, J=6.1, 12.9 Hz), 5.19 (1H, d,J=16.6 Hz), 5.23 (1H, d, J=16.6 Hz), 6.01 (1H, s), 6.37-6.42 (3H, m),7.19 (1H, d, J=8.8 Hz), 7.22 (1H, d, J=5.9 Hz), 7.34 (1H, s), 7.94 (1H,d, J=7.3 Hz), 8.46 (1H, d, J=5.9 Hz), 8.80 (1H, s).

(60b)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(202 mg, 0.32 mmol) prepared in Example 60a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield thetitle compound (135 mg, 88%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.56-2.00 (10H, m), 3.26 (1H, dt, J=2.9,9.0 Hz), 3.90 (3H, s), 4.34-4.45 (1H, m), 6.00 (1H, d, J=2.0 Hz), 6.43(1H, d, J=11.7 Hz), 7.18 (1H, brs), 7.33 (1H, d, J=2.0 Hz), 7.94 (1H, d,J=7.3 Hz), 8.40 (1H, d, J=6.4 Hz), 8.74 (1H, brs).

MS (ESI) m/z: 479 [M+H]+.

Example 615-Ethyl-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(61a)5-Bromo-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50g, 2.06 mmol) prepared in Example 14a,5-bromo-2,4-difluorobenzenesulfonyl chloride (0.90 g, 3.08 mmol),1,4-diazabicyclo[2.2.2]octane (0.46 g, 4.11 mmol) and THF (10 mL), toyield the title compound (0.60 g, 58%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.79 (3H, s), 5.23 (2H, s),6.41-6.43 (2H, m), 6.95 (1H, dd, J=7.8, 9.3 Hz), 7.16 (1H, dd, J=1.5,5.9 Hz), 7.22 (1H, d, J=8.3 Hz), 8.27 (1H, t, J=7.3 Hz), 8.49 (1H, d,J=5.9 Hz), 8.80 (1H, s).

(61b)5-Bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-bromo-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(1.0 g, 2.00 mmol) prepared in Example 61a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.35 g, 2.10 mmol)prepared in Example 8a, sodium hydride (63%; 0.12 g, 3.00 mmol) and DMF(10 mL), to yield the title compound (771 mg, 60%) as a colorlessamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.77-1.98 (4H, m), 2.18-2.38 (2H, m),3.51 (1H, dt, J=5.1, 8.6 Hz), 3.77 (3H, s), 3.79 (3H, s), 3.89 (3H, s),4.60-4.64 (1H, m), 5.23 (2H, s), 6.06 (1H, d, J=2.0 Hz), 6.39-6.41 (2H,m), 6.46 (1H, d, J=11.3 Hz), 7.19-7.21 (2H, m), 7.41 (1H, d, J=1.6 Hz),8.19 (1H, d, J=7.4 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, s).

(61c)N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-5-vinylbenzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using the5-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.31 mmol) prepared in Example 61b,4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.11 mL, 0.62 mmol), a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane mixture (0.04 g, 0.03 mmol), sodium carbonate (0.07g, 0.62 mmol), DMF (8.0 mL) and water (2.0 mL), to yield the titlecompound (113 mg, 63%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.74-1.82 (1H, m), 1.91-1.96 (3H, m),2.16-2.36 (2H, m), 3.42 (1H, dt, J=4.4, 8.3 Hz), 3.76 (3H, s), 3.79 (3H,s), 3.82 (3H, s), 4.65-4.68 (1H, m), 5.25 (2H, s), 5.38 (1H, d, J=11.2Hz), 5.80 (1H, d, J=17.6 Hz), 6.04 (1H, d, J=1.5 Hz), 6.39-6.43 (3H, m),6.88 (1H, d, J=11.2, 18.1 Hz), 7.20 (1H, d, J=8.3 Hz), 7.25-7.26 (1H,m), 7.40 (1H, d, J=2.0 Hz), 8.08 (1H, d, J=8.3 Hz), 8.44 (1H, d, J=6.4Hz), 8.77 (1H, s).

(61d)5-Ethyl-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of theN-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-5-vinylbenzenesulfonamide(29 mg, 0.05 mmol) prepared in Example 61c and triethylsilane (0.10 mL)in dichloromethane (4.0 mL), trifluoroacetic acid (0.5 mL) was added atroom temperature, and the mixture was stirred for 1 hour. The reactionmixture was concentrated to yield a mixture of the title compound and avinyl derivative.

To a solution of this mixture in methanol (0.5 mL) and ethyl acetate(0.5 mL), palladium carbon (10%; 5 mg) was added, and the mixture wasstirred at room temperature for 3 hours under a hydrogen atmosphere. Thereaction solution was filtered through celite, and the residue waspurified with silica gel chromatography to yield the title compound (8.5mg, 38%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.19 (3H, t, J=7.8 Hz), 1.72-1.81 (1H,m), 1.86-1.95 (3H, m), 2.15-2.34 (2H, m), 2.58-2.66 (2H, m), 3.38-3.42(1H, m), 3.83 (3H, s), 4.64-4.67 (1H, m), 6.03 (1H, d, J=1.5 Hz), 6.45(1H, d, J=12.2 Hz), 7.22 (1H, brs), 7.39 (1H, d, J=1.5 Hz), 7.75 (1H, d,J=8.3 Hz), 8.40 (1H, d, J=6.4 Hz), 8.84 (1H, brs).

MS (ESI) m/z: 446 [M+H]+.

Example 625-Cyano-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(62a) Methyl5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-2,4-difluorobenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (378mg, 1.54 mmol) prepared in Example 14a, methyl5-(chlorosulfonyl)-2,4-difluorobenzoate (500 mg, 1.85 mmol),1,4-diazabicyclo[2.2.2]octane (208 mg, 1.85 mmol) and THF (15.0 mL), toyield the title compound (332 mg, 45%) as a pale yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.77 (3H, s), 3.79 (3H, s), 3.98 (3H, s),5.30 (2H, s), 6.40-6.44 (2H, m), 6.96 (1H, t, J=9.4 Hz), 7.17 (1H, d,J=6.8 Hz), 7.22 (1H, d, J=8.8 Hz), 8.48 (1H, d, J=5.9 Hz), 8.70 (1H, t,J=7.8 Hz), 8.78 (1H, s).

(62b) Methyl5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzoate

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the methyl5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-2,4-difluorobenzoate(332 mg, 0.692 mmol) prepared in Example 62a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (115 mg, 0.692 mmol)prepared in Example 8a, sodium hydride (63%; 32.1 mg, 0.830 mmol) andDMF (2.0 mL), to yield the title compound (83.3 mg, 19%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.63-1.99 (4H, m), 2.15-2.39 (2H, m),3.48-3.54 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 3.87 (3H, s), 3.91 (3H,s), 4.63-4.68 (1H, m), 5.23 (2H, s), 6.05 (1H, s), 6.37-6.43 (2H, m),6.50 (1H, d, J=12.2 Hz), 7.17-7.22 (2H, m), 7.40 (1H, s), 8.44 (1H, d,J=5.9 Hz), 8.55 (1H, d, J=8.3 Hz), 8.77 (1H, s).

(62c)5-{[(2,4-Dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzamide

To a solution of the methyl5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzoate(83.3 mg, 0.133 mmol) prepared in Example 62b in THF (2.0 mL), a 5 Maqueous sodium hydroxide solution (2.0 mL) was added, and the reactionsolution was stirred at room temperature for 15 hours. To the reactionsolution, 1 M hydrochloric acid (10 mL) was added with cooling on ice,followed by extraction with ethyl acetate. The thus obtained organiclayer was washed with saturated saline. The organic layer was dried overanhydrous sodium sulfate and vacuum concentrated, and THF (2.0 mL) wasadded to the obtained residue. To the reaction solution,4-methylmorpholine (20.0 μL, 0.183 mmol) and isobutyl chloroformate(23.0 μL, 0.183 mmol) were added in that order with cooling on ice, andthe mixture was stirred for 1 hour with cooling on ice. Then, 28%ammonia water (2.0 mL) was added thereto, and the mixture was stirred atroom temperature for 12 hours. To the reaction solution, saturatedsaline was added, followed by extraction with ethyl acetate. The thusobtained organic layer was washed with saturated saline. The organiclayer was dried over anhydrous sodium sulfate and vacuum concentrated,and the obtained residue was purified with silica gel chromatography(dichloromethane/methanol=85:15) to yield the title compound (64.2 mg,86%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.62-2.08 (4H, m), 2.16-2.42 (2H, m),3.37-3.44 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 3.80 (3H, s), 4.87-4.91(1H, m), 5.30 (2H, s), 6.06 (1H, s), 6.38-6.43 (2H, m), 6.54 (1H, d,J=11.7 Hz), 7.17-7.23 (3H, m), 7.29 (1H, d, J=6.8 Hz), 7.43 (1H, s),8.44 (1H, d, J=5.9 Hz), 8.78 (1H, s), 8.87 (1H, d, J=8.8 Hz).

(62d)5-Cyano-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of the5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzamide(64.3 mg, 0.107 mmol) prepared in Example 62c in dichloromethane (2.0mL), triethylamine (41.0 μL, 0.300 mmol) and trifluoroacetic acid (21.0μL, 0.150 mmol) were added with cooling on ice, and the reactionsolution was stirred at room temperature for 2 hours. To the reactionsolution, triethylamine (41.0 μL, 0.300 mmol) and trifluoroacetic acid(21.0 μL, 0.150 mmol) were added, and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was purified with silicagel chromatography (ethyl acetate) to yield the title compound (32.3 mg,53%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.76-2.04 (4H, m), 2.21-2.41 (2H, m),3.50-3.58 (1H, m), 3.77 (6H, s), 3.90 (3H, s), 4.64-4.72 (1H, m), 5.21(2H, s), 6.06 (1H, s), 6.38-6.44 (2H, m), 6.52 (1H, d, J=11.2 Hz), 7.12(1H, d, J=5.9 Hz), 7.19 (1H, d, J=8.8 Hz), 7.41 (1H, s), 8.26 (1H, d,J=7.8 Hz), 8.48 (1H, d, J=5.9 Hz), 8.79 (1H, s).

(62e)5-Cyano-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-(N-pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-cyano-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(32.3 mg, 0.0545 mmol) prepared in Example 62d, triethylsilane (0.20mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), toyield the title compound (21.5 mg, 89%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.65-1.77 (2H, m), 1.79-1.89 (2H, m),2.19-2.34 (2H, m), 3.48-3.57 (1H, m), 3.80 (3H, s), 4.96-5.07 (1H, m),6.17 (1H, s), 6.90-7.05 (1H, m), 7.25-7.36 (2H, m), 8.07-7.31 (2H, m),8.56 (1H, s).

MS (ESI) m/z: 443 [M+H]+.

Example 632,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(63a)N-(2,4-Dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.455 mmol) prepared in Example 27a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptanol (0.08 g, 0.409 mmol)prepared in Example 9a, sodium hydride (63%; 0.027 g, 0.682 mmol) andDMF (5 mL), to yield the title compound (0.14 g, 52%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.60-1.98 (10H, m), 3.15 (1H, dt, J=2.9,9.3 Hz), 3.77 (3H, s), 3.81 (3H, s), 3.85 (3H, s), 4.36-4.40 (1H, m),5.25 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.27 (2H, d, J=10.7 Hz), 6.41 (1H,dd, J=2.4, 8.3 Hz), 6.44 (1H, d, J=2.0 Hz), 7.16 (1H, dd, J=1.5, 5.9Hz), 7.21 (1H, d, J=8.3 Hz), 7.33 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=5.9Hz), 8.78 (1H, s).

(63b)2,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.14 g, 0.23 mmol) prepared in Example 63a, triethylsilane (0.15 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (60 mg, 40%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.52-1.92 (10H, m), 3.18-3.21 (1H, m),3.76 (3H, s), 4.73-4.77 (1H, m), 6.10 (1H, d, J=2.0 Hz), 6.72 (2H, d,J=11.2 Hz), 6.94 (1H, brs), 7.19 (1H, d, J=1.5 Hz), 8.29 (1H, brs), 8.58(1H, s).

MS (ESI) m/z: 464 [M+H]+.

Example 642-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(64a)N-(2,4-Dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.30 g, 0.69 mmol) prepared in Example 43a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.21 g, 1.15 mmol)prepared in Example 4a, sodium hydride (63%; 0.070 g, 1.65 mmol) and DMF(10 mL), to yield the title compound (0.17 g, 42%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.40-1.64 (4H, m), 1.86-1.88 (1H, m),1.92-1.93 (1H, m), 2.02-2.06 (1H, m), 2.02 (3H, s), 2.23-2.26 (1H, m),2.97-3.02 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.89 (3H, s), 4.01-4.14(1H, m), 5.24 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.36-6.40 (3H, m), 7.19(1H, d, J=8.8 Hz), 7.28 (1H, dd, J=1.5, 5.9 Hz), 7.35 (1H, d, J=2.0 Hz),7.66 (1H, d, J=7.8 Hz), 8.43 (1H, d, J=5.9 Hz), 8.77 (1H, d, J=1.0 Hz).

(64b)2-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.17 g, 0.29 mmol) prepared in Example 64a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (129 mg, 99%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.40-1.60 (4H, m), 1.85-1.87 (1H, m),1.91-1.92 (1H, m), 2.04-2.06 (1H, m), 2.05 (3H, s), 2.23-2.25 (1H, m),2.96-3.02 (1H, m), 3.88 (3H, s), 4.10-4.14 (1H, m), 5.98 (1H, d, J=2.0Hz), 6.42 (1H, d, J=12.2 Hz), 7.23 (1H, d, J=5.4 Hz), 7.34 (1H, d, J=1.5Hz), 7.67 (1H, d, J=8.3 Hz), 8.40 (1H, d, J=6.4 Hz), 8.86 (1H, brs).

MS (ESI) m/z: 446 [M+H]+.

Example 652-Fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(65a) 2,4-Difluoro-3-methylbenzenesulfonyl chloride

To 1,3-difluoro-2-methylbenzene (5.00 g, 39.0 mmol), chlorosulfuric acid(10.5 mL, 158 mmol) was added with cooling on ice, and the mixture wasstirred at room temperature for 5 hours. To the reaction solution, water(100 mL) was added with cooling on ice, followed by extraction withdichloromethane (100 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography to yield the title compound(8.65 g, 98%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.32 (3H, s), 7.05 (1H, dt, d=1.5, 8.8Hz), 7.82-7.87 (1H, m).

(65b)N-(2,4-dimethoxybenzyl)-2,4-difluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.00g, 4.08 mmol) prepared in Example 14a, the2,4-difluoro-3-methylbenzenesulfonyl chloride (1.85 g, 8.15 mmol)prepared in Example 65a, 1,4-diazabicyclo[2.2.2]octane (0.91 g, 8.15mmol) and THF (20 mL), to yield the title compound (1.75 g, 99%) as acolorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.05 (3H, s), 3.78 (3H, s), 3.81 (3H, s),5.28 (2H, s), 6.41-6.44 (2H, m), 6.99 (1H, dt, J=1.5, 9.3 Hz), 7.20 (1H,dd, J=1.5, 5.9 Hz), 7.22 (1H, d, J=8.3 Hz), 7.92-7.96 (1H, m), 8.44 (1H,d, J=5.9 Hz), 8.75 (1H, d, J=1.0 Hz).

(65c)N-(2,4-Dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.30 g, 0.69 mmol) prepared in Example 65b, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.12 g, 0.72 mmol)prepared in Example 8a, sodium hydride (63%; 0.040 g, 1.05 mmol) and DMF(10 mL), to yield the title compound (181 mg, 45%) as a colorlessamorphous solid.

(65d)2-Fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.18 g, 0.31 mmol) prepared in Example 65c, triethylsilane (0.10 mL),trifluoroacetic acid (0.50 mL) and dichloromethane (2.0 mL), to yieldthe title compound (134 mg, 99%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.74-1.95 (4H, m), 2.18 (3H, s),2.21-2.33 (2H, m), 3.40 (1H, dt, J=4.4, 8.3 Hz), 3.82 (3H, s), 4.74-4.77(1H, m), 6.06 (1H, d, J=2.0 Hz), 6.54 (1H, d, J=8.8 Hz), 7.24-7.25 (1H,m), 7.42 (1H, d, J=2.0 Hz), 7.79 (1H, t, J=8.8 Hz), 8.40 (1H, d, J=6.0Hz), 8.88 (1H, brs).

MS (ESI) m/z: 432 [M+H]+.

Example 662-Fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(66a)N-(2,4-Dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.30 g, 0.70 mmol) prepared in Example 65b, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.10 g, 0.70 mmol)prepared in Example 4a, sodium hydride (63%; 0.070 g, 1.65 mmol) and DMF(10 mL), to yield the title compound (175.6 mg, 40%) as a colorlesssolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.43-1.64 (4H, m), 1.86-1.94 (2H, m),1.89 (3H, s), 2.03-2.07 (1H, m), 2.27-2.29 (1H, m), 2.97-3.02 (1H, m),3.76 (3H, s), 3.79 (3H, s), 3.87 (3H, s), 4.27 (1H, dt, J=3.9, 9.8 Hz),5.26 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.39-6.42 (2H, m), 6.55 (1H, d,J=9.3 Hz), 7.19 (1H, d, J=8.3 Hz), 7.25 (1H, dd, J=1.5, 6.4 Hz), 7.35(1H, d, J=2.0 Hz), 7.77 (1H, t, J=8.3 Hz), 8.41 (1H, d, J=6.4 Hz), 8.75(1H, s).

(66b)2-Fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(175.6 mg, 0.29 mmol) prepared in Example 66a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield thetitle compound (122 mg, 93%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.40-1.65 (4H, m), 1.86-1.93 (2H, m),2.05-2.10 (1H, m), 2.18 (3H, s), 2.26-2.28 (1H, m), 2.97-3.02 (1H, m),3.86 (3H, s), 4.26 (1H, dt, J=4.4, 10.3 Hz), 5.99 (1H, d, J=2.0 Hz),6.54 (1H, d, J=9.3 Hz), 7.20 (1H, brs), 7.34 (1H, d, J=1.5 Hz), 7.74(1H, t, J=8.3 Hz), 8.39 (1H, d, J=6.4 Hz), 8.86 (1H, brs).

MS (ESI) m/z: 446 [M+H]+.

Example 674-{[(1S*,2R*)-4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(67a) 6-Iodo-8,8-dimethyl-1,4-dioxaspiro[4.5]dec-6-ene

A solution of 2-iodo-4,4-dimethylcyclohex-2-en-1-one (Synlett, 2005,1263-1266; 5.46 g, 21.8 mmol), ethylene glycol (3.00 g, 48.3 mmol),p-toluenesulfonic acid hydrate (100 mg) in benzene (100 mL) was stirredfor 7 hours under reflux, and the solvent was subjected to azeotropicdistillation with water. After allowing to cool, a saturated aqueoussolution of sodium hydrogencarbonate (100 mL) was added to the reactionsolution, and an organic layer was extracted. The thus obtained organiclayer was dried over anhydrous sodium sulfate. After vacuumconcentration, the residue was purified with silica gel chromatography(hexane/ethyl acetate=95:5) to yield the title compound (5.78 g, 90%) asa colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.03 (6H, s), 1.65-1.68 (2H, m),1.95-1.98 (2H, m), 3.96-3.99 (2H, m), 4.19-4.22 (2H, m), 6.39 (1H, s).

(67b)5-(8,8-Dimethyl-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 33a by using the6-iodo-8,8-dimethyl-1,4-dioxaspiro[4.5]dec-6-ene (1.5 g, 5.10 mmol)prepared in Example 67a,1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (1.00g, 4.81 mmol), tetrakis(triphenylphosphine)palladium (0) (240 mg, 0.208mmol), cesium carbonate (3.40 g, 10.4 mmol), dioxane (7.0 mL) and water(3.0 mL), to yield the title compound (580 mg, 49%) as a brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.11 (6H, s), 1.71-1.74 (2H, m),1.91-1.93 (2H, m), 3.51-3.54 (2H, m), 3.78 (3H, s), 3.79-3.82 (2H, m),5.65 (1H, s), 6.16 (1H, d, J=2.0 Hz), 7.40 (1H, d, J=2.0 Hz).

(67c) 4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one

A solution of the5-(8,8-dimethyl-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole(580 mg, 2.34 mmol) prepared in Example 67b and 2 M hydrochloric acid(2.0 mL) in THF (5.0 mL) was stirred for 1 hour under reflux. Afterallowing to cool, a 1 M aqueous sodium hydroxide solution (5.0 mL) wasadded to the reaction solution, followed by extraction with ethylacetate (50 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=1:1) toyield the title compound (432 mg, 91%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.27 (6H, s), 1.99 (2H, t, J=6.7 Hz),2.63 (2H, t, J=7.0 Hz), 3.68 (3H, s), 6.13 (1H, d, J=2.0 Hz), 6.78 (1H,s), 7.44 (1H, d, J=2.0 Hz).

(67d) 4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

To a solution of the4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one (432 mg,2.12 mmol) prepared in Example 67c in methanol (6.0 mL), sodiumborohydride (200 mg, 5.29 mmol) was added with cooling on ice, and thereaction solution was stirred at room temperature for 1 hour. To thereaction solution, a saturated aqueous solution of ammonium chloride (20mL) was added, followed by extraction with dichloromethane (50 mL). Thethus obtained organic layer was dried over anhydrous sodium sulfate andvacuum concentrated to yield a mixture of the title compound and anallyl alcohol derivative.

A solution of this mixture and palladium hydroxide carbon (10%; 300 mg)in ethanol (6.0 mL) was stirred at room temperature for 3 hours under ahydrogen atmosphere. The reaction solution was filtered through celite,and the residue was purified with silica gel chromatography(dichloromethane/methanol=97:3) to yield the title compound (347 mg,79%) in the form of a trans/cis (3:1) mixture.

(67e)N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(337 mg, 0.767 mmol) prepared in Example 14b, the4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (160 mg, 0.768mmol) prepared in Example 67d, sodium hydride (63%; 80 mg, 2.10 mmol)and DMF (4.0 mL), to yield the title compound (293 mg, 61%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.04 (3H, s), 1.12 (3H, s), 1.41-1.47(1H, m), 1.57-1.62 (2H, m), 1.68-1.81 (2H, m), 2.04-2.08 (1H, m),3.21-3.26 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.91 (3H, s), 4.08 (1H,dt, J=4.4, 11.2 Hz), 5.19 (1H, d, J=17.1 Hz), 5.23 (1H, d, J=17.1 Hz),6.01 (1H, d, J=2.0 Hz), 6.39-6.41 (2H, m), 6.45 (1H, dd, J=6.4, 11.2Hz), 7.17-7.18 (2H, m), 7.33 (1H, d, J=2.0 Hz), 7.67 (1H, dd, J=6.8,10.3 Hz), 8.45 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=1.0 Hz).

(67f)4-{[(1S*,2R*)-4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(293 mg, 0.467 mmol) prepared in Example 67e, triethylsilane (0.40 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield thetitle compound (198 mg, 89%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 0.97 (3H, s), 1.08 (3H, s), 1.44-1.69(5H, m), 1.98-2.02 (1H, m), 3.26 (1H, dt, J=4.4, 10.3 Hz), 3.79 (3H, s),4.52 (1H, dt, J=4.4, 10.3 Hz), 6.05 (1H, d, J=2.0 Hz), 6.94 (1H, brs),7.18 (1H, d, J=2.0 Hz), 7.26 (1H, brs), 7.61 (1H, brs), 8.24 (1H, brs),8.56 (1H, s).

MS (ESI) m/z: 478 [M+H]+.

Example 684-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(68a)N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-1′-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(243 mg, 0.559 mmol) prepared in Example 43a, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(165 mg, 0.559 mmol) prepared in Example 34b, sodium hydride (63%; 64.4mg, 0.671 mmol) and DMF (8.0 mL), to yield the title compound (291 mg,73%) as a pale yellow solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.45-1.68 (8H, m), 1.79-2.26 (6H, m),2.05 (3H, s), 3.62-3.69 (2H, m), 3.76 (3H, s), 3.79 (3H, s), 3.89-4.01(1H, m), 4.10-4.18 (1H, m), 5.25 (2H, s), 5.30-5.34 (1H, m), 6.38-6.47(3H, m), 7.19 (1H, d, J=8.3 Hz), 7.29 (1H, dt, J=1.5, 6.4 Hz), 7.43 (1H,d, J=22.9 Hz), 7.65 (1H, dd, J=3.4, 8.3 Hz), 8.44 (1H, d, J=5.9 Hz),8.77 (1H, s).

(68b)2-Fluoro-5-methyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(291 mg, 0.409 mmol) prepared in Example 68a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (172 mg, 88%) as a pale yellowsolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.43-1.52 (3H, m), 1.70-1.72 (1H, m),1.84-1.97 (2H, m), 1.97 (3H, s), 2.09-2.21 (2H, m), 3.64-3.69 (1H, m),4.15-4.17 (1H, m), 6.37 (1H, d, J=12.2 Hz), 7.49 (1H, brs), 7.59 (1H, d,J=8.3 Hz), 7.74 (1H, s), 8.49 (1H, d, J=6.4 Hz), 8.98 (1H, s).

(68c)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

A solution of the2-fluoro-5-methyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(40 mg, 0.0840 mmol) prepared in Example 68b and palladium carbon (10%;30 mg) in methanol (1.0 mL) and ethyl acetate (1.0 mL) was stirred at60° C. for 5 hours under a hydrogen atmosphere. The reaction solutionwas filtered through celite, and the residue was purified with silicagel chromatography (dichloromethane/methanol) to yield the titlecompound (10.8 mg, 29%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.25-1.61 (4H, m), 1.79-1.91 (2H, m),2.05-2.17 (2H, m), 2.16 (3H, s), 2.67-2.72 (1H, m), 4.00 (1H, dt, J=3.9,9.8 Hz), 6.40 (1H, d, J=12.2 Hz), 7.16 (1H, s), 7.29 (1H, brs), 7.66(1H, d, J=8.8 Hz), 8.41 (1H, d, J=6.4 Hz), 8.77 (1H, brs).

MS (ESI) m/z: 447 [M+H]+.

Example 694-{[(1S*,2R*)-2-(2-Aminopyridin-3-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(69a) 3-Cyclohex-1-en-1-ylpyridin-2-amine

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using 3-bromopyridin-2-amine (0.42 g, 2.40 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g,2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12mmol), cesium carbonate (1.72 g, 5.29 mmol), 1,4-dioxane (8.0 mL) andwater (4.0 mL), to yield the title compound (403.3 mg, 96%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.67-1.71 (2H, m), 1.74-1.79 (2H, m),2.15-2.19 (2H, m), 2.20-2.24 (2H, m), 4.55 (2H, brs), 5.82-5.84 (1H, m),6.64 (1H, dd, J=4.9, 6.8 Hz), 7.21 (1H, dd, J=2.0, 7.3 Hz), 7.95 (1H,dd, J=1.0, 6.4 Hz).

(69b) (1S*,2R*)-2-(2-Aminopyridin-3-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the 3-cyclohex-1-en-1-ylpyridin-2-amine (0.40 g,2.31 mmol) prepared in Example 69a, a borane-THF complex (0.95 M; 7.30mL, 6.94 mmol), sodium perborate tetrahydrate (0.93 g, 6.01 mmol), THF(2.3 mL) and water (3.5 mL), to yield the title compound (45.4 mg, 10%)as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.27-1.51 (4H, m), 1.77-1.86 (3H, m),2.08-2.10 (1H, m), 2.47 (1H, t, J=10.3 Hz), 3.55-3.59 (1H, m), 6.62-6.65(1H, m), 7.37 (1H, d, J=7.3 Hz), 7.73 (1H, d, J=3.9 Hz).

(69c)4-{[(1S*,2R*)-2-(2-Aminopyridin-3-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.11 g, 0.25 mmol) prepared in Example 14b, the(1S*,2R*)-2-(2-aminopyridin-3-yl)cyclohexanol (0.05 g, 0.25 mmol)prepared in Example 69b, sodium hydride (63%; 0.01 g, 0.38 mmol) and DMF(1.3 mL), to yield the title compound (34 mg, 22%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41-1.76 (4H, m), 1.88-1.97 (3H, m),2.27-2.29 (1H, m), 2.91-2.96 (1H, m), 3.76 (6H, s), 4.19 (1H, dt, J=4.4,10.7 Hz), 4.72 (2H, brs), 5.19 (2H, s), 6.38-6.41 (2H, m), 6.51 (1H, dd,J=6.4, 11.2 Hz), 6.66 (1H, dd, J=4.9, 7.8 Hz), 7.17-7.19 (2H, m), 7.37(1H, dd, J=1.5, 7.3 Hz), 7.66 (1H, dd, J=6.8, 10.3 Hz), 7.92 (1H, dd,J=2.0, 4.9 Hz), 8.45 (1H, d, J=5.9 Hz), 8.77 (1H, d, J=1.5 Hz).

(69d)4-{[(1S*,2R*)-2-(2-Aminopyridin-3-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-2-(2-aminopyridin-3-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.06 g, 0.09 mmol) prepared in Example 69c, triethylsilane (0.07 mL),trifluoroacetic acid (0.09 mL) and dichloromethane (0.90 mL), to yieldthe title compound (34.2 mg, 82%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.47-1.69 (4H, m), 1.82-1.92 (3H, m),2.27-2.30 (1H, m), 3.04-3.09 (1H, m), 4.58 (1H, dt, J=4.4, 9.8 Hz), 6.66(1H, dd, J=6.8, 7.8 Hz), 6.88 (1H, dd, J=1.0, 6.4 Hz), 6.99 (1H, dd,J=6.4, 11.2 Hz), 7.60 (1H, dd, J=6.8, 10.7 Hz), 7.69-7.73 (2H, m), 8.14(1H, d, J=6.4 Hz), 8.44 (1H, s).

MS (ESI) m/z: 462 [M+H]+.

Example 702,5-Difluoro-4-{[(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(70a) 3-(Cyclohex-1-en-1-yl)-2-methylpyridine

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using 3-bromo-2-methylpyridine (0.41 g, 2.40 mmol),2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g,2.40 mmol), tetrakis(triphenylphosphine) palladium (0)(0.14 g, 0.12mmol), cesium carbonate (1.72 g, 5.29 mmol), 1,4-dioxane (8.0 mL) andwater (4.0 mL), to yield the title compound (353.2 mg, 85%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.67-1.78 (4H, m), 2.17-2.19 (4H, m),2.51 (3H, s), 5.59-5.61 (1H, m), 7.06 (1H, dd, J=4.9, 7.8 Hz), 7.34 (1H,dd, J=2.0, 7.8 Hz), 8.37 (1H, dd, J=2.0, 4.9 Hz).

(70b) (1S*,2R*)-2-(2-Methylpyridin-3-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the 3-(cyclohex-1-en-1-yl)-2-methylpyridine (0.35g, 2.03 mmol) prepared in Example 70a, a borane-THF complex (0.95 M;6.40 mL, 6.08 mmol), sodium perborate tetrahydrate (0.81 g, 5.27 mmol),THF (2.0 mL) and water (3.0 mL), to yield the title compound (106.3 mg,27%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.24-1.47 (4H, m), 1.76-1.87 (3H, m),2.13-2.15 (1H, m), 2.56 (3H, s), 2.71-2.76 (1H, m), 3.72-3.77 (1H, m),7.10 (1H, dd, J=4.9, 7.8 Hz), 7.55 (1H, dd, J=1.5, 7.8 Hz), 8.24 (1H,dd, J=1.5, 4.9 Hz).

(70c)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.25 g, 0.57 mmol) prepared in Example 14b, the(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexanol (0.11 g, 0.57 mmol)prepared in Example 70b, sodium hydride (63%; 0.03 g, 0.85 mmol) and DMF(2.8 mL), to yield the title compound (45.7 mg, 13%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.43-1.60 (4H, m), 1.88-1.98 (3H, m),2.27-2.30 (1H, m), 2.67 (3H, s), 3.15-3.20 (1H, m), 3.76 (3H, s), 3.77(3H, s), 4.29 (1H, dt, J=4.4, 10.3 Hz), 5.20 (2H, s), 6.38-6.43 (2H, m),6.50 (1H, dd, J=5.9, 10.7 Hz), 7.03 (1H, dd, J=4.9, 7.8 Hz), 7.16-7.22(2H, m), 7.44 (1H, dd, J=2.0, 8.3 Hz), 7.61 (1H, dd, J=6.8, 10.3 Hz),8.29 (1H, dd, J=1.5, 3.4 Hz), 8.44 (1H, d, J=5.4 Hz), 8.77 (1H, s).

(70d)2,5-Difluoro-4-{[(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.05 g, 0.08 mmol) prepared in Example 70c, triethylsilane (0.06 mL),trifluoroacetic acid (0.08 mL) and dichloromethane (0.75 mL), to yieldthe title compound (34 mg, 98%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.45-1.75 (4H, m), 1.84-1.94 (3H, m),2.29-2.31 (1H, m), 2.65 (3H, s), 3.18-3.24 (1H, m), 4.61 (1H, dt, J=3.9,9.8 Hz), 6.95 (1H, dd, J=1.0, 6.4 Hz), 6.99 (1H, dd, J=6.8, 11.7 Hz),7.16 (1H, dd, J=4.9, 7.8 Hz), 7.57 (1H, dd, J=6.8, 10.7 Hz), 7.82 (1H,dd, J=2.0, 7.8 Hz), 8.14 (1H, dd, J=1.5, 4.9 Hz), 8.21 (1H, d, J=6.4Hz), 8.49 (1H, s).

MS (ESI) m/z: 461 [M+H]+.

Example 714-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(71a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(196 mg, 0.430 mmol) prepared in Example 20a, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(127 mg, 0.430 mmol) prepared in Example 34b, sodium hydride (63%; 49.5mg, 0.516 mmol) and DMF (6.0 mL), to yield the title compound (264 mg,84%) as a pale yellow amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.45-1.69 (8H, m), 1.81-2.24 (6H, m),3.61-3.70 (2H, m), 3.77 (3H, s), 3.78 (3H, s), 3.92-4.00 (1H, m),4.27-4.32 (1H, m), 5.22 (2H, s), 5.32-5.36 (1H, m), 6.38-6.41 (2H, m),6.56 (1H, t, J=12.2 Hz), 7.18 (1H, d, J=9.3 Hz), 7.20-7.23 (1H, m), 7.47(1H, d, J=29.8 Hz), 7.91 (1H, dd, J=5.4, 7.3 Hz), 7.47 (1H, d, J=5.9Hz), 8.79 (1H, s).

(71b)5-Chloro-2-fluoro-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(264 mg, 0.362 mmol) prepared in Example 71a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (162 mg, 90%) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.31-1.57 (4H, m), 1.71-1.80 (2H, m),1.96-1.99 (1H, m), 2.17-2.19 (1H, m), 3.48-3.53 (1H, m), 4.56-4.61 (1H,m), 7.24-7.31 (2H, m), 7.73-7.76 (2H, m), 7.90-7.91 (1H, m), 8.56 (1H,s).

(71c)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

A solution of the5-chloro-2-fluoro-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.05 g, 0.101 mmol) prepared in Example 71b, an iron powder (56 mg,1.01 mol) and a saturated aqueous solution of ammonium chloride (2.0 mL)in ethanol (2.0 mL) was stirred for 15 hours under heated reflux. Afterallowing to cool, the reaction solution was filtered through celite, andthe filtrate was subjected to extraction with ethyl acetate (100 mL).The organic layer was dried over anhydrous sodium sulfate and vacuumconcentrated, and the residue was purified with silica gelchromatography (dichloromethane/methanol) to yield the title compound(29.9 mg, 64%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.38-1.54 (3H, m), 1.66-1.75 (1H, m),1.80-1.88 (2H, m), 1.97-2.01 (2H, m), 2.72-2.77 (1H, m), 4.38 (1H, dt,J=3.9, 5.9 Hz), 6.95-6.99 (3H, m), 7.92 (1H, d, J=7.8 Hz), 8.24 (1H, d,J=5.9 Hz), 8.52 (1H, s).

MS (ESI) m/z: 467 [M+H]+.

Example 724-{[(1S*,2R*)-5,5-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(72a) 6-Iodo-9,9-dimethyl-1,4-dioxaspiro[4.5]dec-6-ene

The reaction and aftertreatment were conducted in the same manner as inExample 67a by using 2-iodo-5,5-dimethylcyclohex-2-en-1-one (J. Org.Chem., 1994, 59, 5393-5396; 6.10 g, 24.4 mmol), ethylene glycol (3.00 g,48.3 mmol), p-toluenesulfonic acid hydrate (230 mg, 1.22 mmol) andbenzene (70 mL), to yield the title compound (3.33 g, 46%) as a brownoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.01 (6H, s), 1.84 (2H, s), 1.96 (2H, d,J=3.9 Hz), 3.95-3.98 (2H, m), 4.18-4.21 (2H, m), 6.59 (1H, t, J=4.4 Hz).

(72b)5-(9,9-Dimethyl-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using the6-iodo-9,9-dimethyl-1,4-dioxaspiro[4.5]dec-6-ene (1.4 g, 4.76 mmol)prepared in Example 72a,1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (1.00g, 4.81 mmol), tetrakis(triphenylphosphine)palladium (0) (240 mg, 0.208mmol), cesium carbonate (3.40 g, 10.4 mmol), 1,4-dioxane (10 mL) andwater (5.0 mL), to yield the title compound (758 mg, 64%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.09 (6H, s), 1.80 (2H, s), 2.07 (2H, d,J=3.9 Hz), 3.44-3.47 (2H, m), 3.77-3.79 (2H, m), 3.80 (3H, s), 5.88 (1H,t, J=3.9 Hz), 6.17 (1H, d, J=1.5 Hz), 7.41 (1H, d, J=2.0 Hz).

(72c) 5,5-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one

The reaction and aftertreatment were conducted in the same manner as inExample 67c by using the5-(9,9-dimethyl-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole(758 mg, 3.05 mmol) prepared in Example 72b, 2 M hydrochloric acid (2.0mL) and THF (5.0 mL), to yield the title compound (581 mg, 93%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.14 (6H, s), 1.58 (2H, s), 2.46 (2H, d,J=2.9 Hz), 3.70 (3H, s), 6.14 (1H, d, J=1.5 Hz), 6.98 (1H, t, J=3.9 Hz),7.44 (1H, d, J=1.5 Hz).

(72d) (1S*,2R*)-5,5-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

To a solution of the5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one (581 mg,2.84 mmol) prepared in Example 72c in methanol (6.0 mL), sodiumborohydride (200 mg, 5.29 mmol) was added with cooling on ice, and thereaction solution was stirred at room temperature for 30 minutes. To thereaction solution, a saturated aqueous solution of ammonium chloride (50mL) was added, followed by extraction with ethyl acetate (100 mL). Thethus obtained organic layer was dried over anhydrous sodium sulfate.After vacuum concentration, the residue was purified with silica gelchromatography (dichloromethane/methanol=98:2) to yield the titlecompound (40 mg, 6.8%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.01 (3H, s), 1.02 (3H, s), 1.29-1.34(2H, m), 1.44-1.48 (1H, m), 1.55-1.64 (1H, m), 1.72-1.83 (2H, m),2.47-2.52 (1H, m), 3.81 (1H, dt, J=4.4, 11.2 Hz), 3.84 (3H, s), 6.08(1H, d, J=1.5 Hz), 7.42 (1H, d, J=1.5 Hz).

(72e)N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(85 mg, 0.193 mmol) prepared in Example 14b, the(1S*,2R*)-5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (40 mg,0.192 mmol) prepared in Example 72d, sodium hydride (63%; 30 mg, 0.788mmol) and DMF (2.0 mL), to yield the title compound (100 mg, 83%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.06 (3H, s), 1.10 (3H, s), 1.39-1.48(2H, m), 1.55-1.62 (1H, m), 1.81-1.96 (3H, m), 2.91-2.96 (1H, m), 3.77(3H, s), 3.78 (3H, s), 3.90 (3H, s), 4.30 (1H, dt, J=3.9, 11.2 Hz), 5.19(1H, d, J=16.6 Hz), 5.24 (1H, d, J=17.1 Hz), 6.05 (1H, d, J=2.0 Hz),6.38-6.42 (3H, m), 7.18-7.20 (2H, m), 7.36 (1H, d, J=1.5 Hz), 7.67 (1H,dd, J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, d, J=1.0 Hz).

(72f)4-{[(1S*,2R*)-5,5-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(100 mg, 0.159 mmol) prepared in Example 72e, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (70 mg, 92%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 0.98 (3H, s), 1.09 (3H, s), 1.36-1.43(3H, m), 1.68-1.90 (3H, m), 3.01 (1H, dt, J=4.4, 11.7 Hz), 3.77 (3H, s),4.68 (1H, dt, J=3.9, 10.7 Hz), 6.21 (1H, d, J=2.0 Hz), 6.98 (1H, brs),7.08 (1H, dd, J=6.4, 11.2 Hz), 7.19 (1H, d, J=2.0 Hz), 7.60-7.63 (1H,m), 8.24 (1H, brs), 8.57 (1H, s).

MS (ESI) m/z: 478 [M+H]+.

Example 734-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(73a)N-(2,4-Dimethoxybenzyl)-2-fluoro-3-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(155 mg, 0.356 mmol) prepared in Example 65b, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(105 mg, 0.356 mmol) prepared in Example 34b, sodium hydride (63%; 41.0mg, 0.427 mmol) and DMF (6.0 mL), to yield the title compound (209 mg,83%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.48-1.65 (8H, m), 1.82-2.28 (6H, m),2.05 (3H, s), 3.58-3.68 (2H, m), 3.77 (3H, s), 3.80 (3H, s), 3.87-4.00(1H, m), 4.29-4.35 (1H, m), 5.27 (2H, s), 5.30-5.33 (1H, m), 6.39-6.43(2H, m), 6.65 (1H, dd, J=8.8, 15.1 Hz), 7.19 (1H, d, J=8.8 Hz),7.22-7.24 (1H, m), 7.43 (1H, d, J=24.4 Hz), 7.81 (1H, dd, J=8.8, 17.6Hz), 7.41 (1H, d, J=5.9 Hz), 8.74 (1H, s).

(73b)2-Fluoro-3-methyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(209 mg, 0.294 mmol) prepared in Example 73a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (139 mg, 99%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.46-1.71 (4H, m), 1.82-1.93 (2H, m),1.83 (3H, s), 2.06-2.09 (1H, m), 2.26-2.29 (1H, m), 3.57-3.63 (1H, m),4.55 (1H, dt, J=4.4, 10.7 Hz), 6.85 (1H, d, J=8.8 Hz), 7.08 (1H, d,J=6.4 Hz), 7.69 (1H, s), 7.77 (1H, t, J=8.8 Hz), 8.35 (1H, d, J=6.4 Hz),8.62 (1H, s).

(73c)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 68c by using the2-fluoro-3-methyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(139 mg, 0.292 mmol) prepared in Example 73b, palladium carbon (10%; 18mg), methanol (1.0 mL) and ethyl acetate (1.0 mL), to yield the titlecompound (34 mg, 26%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.42-1.66 (3H, m), 1.78-1.82 (1H, m),1.85-1.89 (1H, m), 1.98-2.02 (2H, m), 2.15 (3H, s), 2.19-2.23 (1H, m),2.73-2.78 (1H, m), 4.40 (1H, dt, J=3.9, 9.8 Hz), 6.83 (1H, d, J=8.8 Hz),7.04 (1H, d, J=6.4 Hz), 7.17 (1H, s), 7.74 (1H, t, J=8.3 Hz), 8.30 (1H,d, J=6.4 Hz), 8.55 (1H, s).

MS (ESI) m/z: 447 [M+H]+.

Example 742,5-Difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamideNa salt

The reaction and aftertreatment were conducted in the same manner as inExample 5c by using the2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(114 mg, 0.252 mmol) prepared in Example 1b, a 1 M sodium hydroxidesolution (0.252 mL, 0.252 mol) and methanol (3.0 mL), to yield the titlecompound (119 mg, 99%) as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.31-1.61 (4H, m), 1.70-1.83 (3H, m),2.14-2.17 (1H, m), 2.76-2.83 (1H, m), 4.74 (1H, dt, J=3.9, 10.1 Hz),7.07-7.34 (7H, m), 7.87 (1H, s).

Example 752,5-Difluoro-4-{[(1R,2S)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(75a)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by usingN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(WO 2010/079443; 126 mg, 0.283 mmol), (1R,2S)-2-phenylcyclohexanol (50.0mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0mL), to yield the title compound (53.6 mg, 31%) as a colorless oil.

(75b)2,5-Difluoro-4-{[(1R,2S)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(53.6 mg, 0.0891 mmol) prepared in Example 75a, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (40.2 mg, 99%) as a colorless solid.

[α]_(D) ²⁵=56.9 (c 0.232, DMSO).

Example 762,5-Difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamideNa salt

The reaction and aftertreatment were conducted in the same manner as inExample 5c by using the2,5-difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(386 mg, 0.855 mmol) prepared in Example 2b, and a 1 M sodium hydroxidesolution (0.855 mL, 0.855 mol), to yield the title compound (386 mg,99%) as a colorless solid.

[α]_(D) ²⁵=−44.1 (c 1.06, DMSO).

Example 772,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamideNa salt

The reaction and aftertreatment were conducted in the same manner as inExample 5c by using the2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(15.3 mg, 0.035 mmol) prepared in Example 14d, and a 1 M sodiumhydroxide solution (0.035 mL, 0.035 mol), to yield the title compound(11.0 mg, 68%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.75-1.99 (4H, m), 2.24-2.32 (2H, m),3.48-3.52 (1H, m), 3.81 (3H, s), 4.78-4.82 (1H, m), 6.19 (1H, d, J=2.0Hz), 6.71 (1H, d, J=7.3 Hz), 6.81 (1H, dd, J=6.4, 10.7 Hz), 7.35 (1H, d,J=2.0 Hz), 7.65 (1H, dd, J=6.4, 10.7 Hz), 8.00 (1H, d, J=6.4 Hz), 8.31(1H, s).

Example 782,5-Difluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(78a)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

TheN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamideprepared in Example 14c was optically resolved with CHIRALPAK AD (DaicelCorp.; hexane/isopropanol=4:1), to yield the title compound as acolorless oil.

(78b)2,5-Difluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(436 mg, 0.74 mmol) prepared in Example 78a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (239 mg, 74%) as a colorless solid.

[α]_(D) ²⁵=−72.7 (c 1.04, DMSO).

Example 793-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(79a)3-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.00g, 4.07 mmol) prepared in Example 14a,3-chloro-2,4-difluorobenzenesulfonyl chloride (1.51 g, 6.11 mmol),1,4-diazabicyclo[2.2.2]octane (0.69 g, 6.11 mmol) and THF (20 mL), toyield the title compound (0.983 g, 53%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.78 (3H, s), 3.81 (3H, s), 5.25 (2H, s),6.41-6.43 (2H, m), 7.11-7.15 (2H, m), 7.22 (1H, d, J=8.8 Hz), 8.01-8.05(1H, m), 8.47 (1H, d, J=5.9 Hz), 8.75 (1H, d, J=1.0 Hz).

(79b)3-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the3-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.30 g, 0.69 mmol) prepared in Example 79a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.12 g, 0.66 mmol)prepared in Example 4a, sodium hydride (63%; 0.050 g, 1.31 mmol) and DMF(2.0 mL), to yield the title compound (314 mg, 77%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41-1.63 (4H, m), 1.88-1.97 (2H, m),2.07-2.09 (1H, m), 2.23-2.26 (1H, m), 3.03-3.08 (1H, m), 3.77 (3H, s),3.78 (3H, s), 3.92 (3H, s), 4.29 (1H, dt, J=3.9, 10.3 Hz), 5.21 (1H, d,J=17.1 Hz), 5.26 (1H, d, J=17.1 Hz), 6.05 (1H, d, J=2.0 Hz), 6.39-6.41(2H, m), 6.60 (1H, d, J=9.3 Hz), 7.16 (1H, dd, J=1.5, 5.9 Hz), 7.19 (1H,d, J=9.3 Hz), 7.36 (1H, d, J=2.0 Hz), 7.81 (1H, dd, J=7.8, 8.8 Hz), 8.44(1H, d, J=5.9 Hz), 8.76 (1H, s).

(79c)3-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(314 mg, 0.51 mmol) prepared in Example 79b, triethylsilane (0.50 mL),trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield thetitle compound (183 mg, 77%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-1.70 (4H, m), 1.87-1.95 (2H, m),2.06-2.10 (1H, m), 2.22-2.25 (1H, m), 3.03-3.08 (1H, m), 3.92 (3H, s),4.28 (1H, dt, J=4.4, 10.7 Hz), 6.04 (1H, d, J=2.0 Hz), 6.61 (1H, dd,J=1.0, 9.3 Hz), 7.20-7.21 (1H, m), 7.36 (1H, d, J=2.0 Hz), 7.78 (1H, t,J=7.8 Hz), 8.35 (1H, d, J=6.4 Hz), 8.81 (1H, s).

MS (ESI) m/z: 466 [M+H]+.

Example 803-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(80a)3-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the3-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(463 mg, 1.02 mmol) prepared in Example 79a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (169 mg, 1.02 mmol)prepared in Example 8a, sodium hydride (63%; 50 mg, 1.31 mmol) and DMF(3.0 mL), to yield the title compound (347 mg, 57%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.80-1.98 (4H, m), 2.22-2.35 (2H, m),3.50 (1H, dt, J=4.9, 8.8 Hz), 3.76 (3H, s), 3.80 (3H, s), 3.87 (3H, s),4.73-4.76 (1H, m), 5.24 (1H, d, J=17.1 Hz), 5.29 (1H, d, J=17.1 Hz),6.08 (1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.63 (1H, dd, J=1.0, 8.8 Hz),7.18 (1H, dd, J=1.5, 5.9 Hz), 7.20 (1H, d, J=7.8 Hz), 7.42 (1H, d, J=1.5Hz), 7.88 (1H, dd, J=7.8, 8.8 Hz), 8.44 (1H, d, J=6.4 Hz), 8.76 (1H, d,J=1.0 Hz).

(80b)3-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(344 mg, 0.31 mmol) prepared in Example 80a, triethylsilane (0.50 mL),trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield thetitle compound (227 mg, 88%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.78-1.98 (4H, m), 2.22-2.35 (2H, m),3.49 (1H, dt, J=4.9, 8.3 Hz), 3.86 (3H, s), 4.72-4.75 (1H, m), 6.07 (1H,d, J=2.0 Hz), 6.64 (1H, d, J=7.8 Hz), 7.24-7.25 (1H, m), 7.42 (1H, d,J=2.0 Hz), 7.86 (1H, dd, J=7.8, 8.8 Hz), 8.37 (1H, d, J=6.4 Hz), 8.84(1H, brs).

MS (ESI) m/z: 452 [M+H]+.

Example 812-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(81a)N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(200 mg, 0.459 mmol) prepared in Example 43a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(114 mg, 0.459 mmol) prepared in Example 33b, sodium hydride (63%; 27mg, 0.680 mmol) and DMF (7.0 mL), to yield the title compound (170 mg,56%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41-1.69 (8H, m), 1.80-2.18 (6H, m),2.15 (3H, s), 2.85-2.90 (1H, m), 3.62-3.67 (1H, m), 3.76 (3H, s), 3.79(3H, s), 3.98-4.02 (2H, m), 5.25 (2H, s), 5.26-5.28 (1H, m), 6.37-6.42(3H, m), 7.19 (1H, d, J=8.3 Hz), 7.30 (1H, dt, J=1.5, 5.9 Hz), 7.38 (1H,d, J=6.4 Hz), 7.41 (1H, s), 7.68 (1H, d, J=8.3 Hz), 8.43 (1H, d, J=5.9Hz), 8.77 (1H, s).

(81b)2-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide(150 mg, 0.22 mmol) prepared in Example 81a, triethylsilane (0.15 mL),trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol(1.5 mL), to yield the title compound (70 mg, 72%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.30-1.37 (2H, m), 1.45-1.75 (4H, m),1.92-1.94 (1H, m), 2.06 (3H, s), 2.06-2.10 (1H, m), 2.75-2.80 (1H, m),4.35 (1H, dt, J=3.9, 9.8 Hz), 6.97 (1H, d, J=12.7 Hz), 6.99 (1H, brs),7.41 (2H, s), 7.62 (1H, d, J=8.3 Hz), 8.31 (1H, brs), 8.58 (1H, s).

MS (ESI) m/z: 432 [M+H]+.

Example 824-{[(1S*,2R*)-2-(3-Aminopyridazin-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(82a)6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-6-ene

To a solution of 6-iodo-1,4-dioxaspiro[4.5]dec-6-ene (Synlett, 2008,1086-1090; 2.70 g, 10.2 mmol) in THF (30 mL), butyl lithium (1.65 Msolution in hexane; 6.7 mL, 11.1 mmol) was added at −78° C. The reactionsolution was stirred at −78° C. for 1 hour. Then,4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (4.0 mL, 19.8mmol) was added thereto, and the mixture was stirred at −78° C. for 2hours. To the reaction solution, water (50 mL) was added, followed byextraction with ethyl acetate (50 mL). The thus obtained organic layerwas dried over anhydrous sodium sulfate. After vacuum concentration, theresidue was purified with silica gel chromatography (hexane/ethylacetate=9:1) to yield the title compound (1.52 g, 56%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.26 (12H, s), 1.72-1.80 (4H, m),2.07-2.10 (2H, m), 3.93-3.95 (2H, m), 4.16-4.18 (2H, m), 6.71 (1H, t,J=3.4 Hz).

(82b) 6-Chloro-4-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)pyridazin-3-amine

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using the6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-6-ene(0.64 g, 2.40 mmol) prepared in Example 82a,4-bromo-6-chloropyridazin-3-amine (0.50 g, 2.40 mmol),tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), cesiumcarbonate (1.72 g, 5.29 mmol), dioxane (8.0 mL) and water (4.0 mL), toyield the title compound (275.7 mg, 43%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.85-1.89 (4H, m), 2.20-2.23 (2H, m),3.70-3.73 (2H, m), 3.89-3.92 (2H, m), 5.72 (2H, brs), 6.03 (1H, t, J=3.9Hz), 7.05 (1H, s).

(82c) 4-(1,4-Dioxaspiro[4.5]dec-6-en-6-yl)pyridazin-3-amine

A solution of the6-chloro-4-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)pyridazin-3-amine (0.10 g,0.37 mmol) prepared in Example 82b, ammonium formate (0.14 g, 2.24 mmol)and palladium carbon (10%; 0.10 g) in ethanol (3.7 mL) was stirred at80° C. for 4 hours. After allowing to cool, the reaction solution wasfiltered through celite and concentrated to yield the title compound ina crude form.

(82d) 2-(3-Aminopyridazin-4-yl)cyclohex-2-en-1-one

The reaction and aftertreatment were conducted in the same manner as inExample 67c by using the crude4-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)pyridazin-3-amine prepared inExample 82c, 2 M hydrochloric acid (0.37 mL) and THF (0.92 mL), to yieldthe title compound (69 mg, 99%, 2 steps) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.13-2.18 (2H, m), 2.58-2.64 (4H, m),4.97 (2H, brs), 6.99 (1H, d, J=4.9 Hz), 7.19 (1H, t, J=4.4 Hz), 8.61(1H, d, J=4.4 Hz).

(82e) (1S*,2R*)-2-(3-Aminopyridazin-4-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 72d by using the 2-(3-aminopyridazin-4-yl)cyclohex-2-en-1-one(40 mg, 0.20 mmol) prepared in Example 82d, sodium borohydride (20 mg,0.59 mmol) and methanol (2.0 mL), to yield the title compound (39 mg,99%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.23-1.95 (7H, m), 2.10-2.14 (1H, m),2.52-2.57 (1H, m), 3.58-3.63 (1H, m), 5.43 (2H, brs), 7.07 (1H, d, J=4.9Hz), 8.33 (1H, d, J=4.9 Hz).

(82f)4-{[(1S*,2R*)-2-(3-Aminopyridazin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(90 mg, 0.20 mmol) prepared in Example 14b, the(1S*,2R*)-2-(3-aminopyridazin-4-yl)cyclohexanol (40 mg, 0.20 mmol)prepared in Example 82e, sodium hydride (63%; 10 mg, 0.31 mmol) and DMF(1.0 mL), to yield the title compound (45.6 mg, 36%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.59 (3H, m), 1.68-1.76 (1H, m),1.91-1.98 (3H, m), 2.30-2.33 (1H, m), 2.91-2.97 (1H, m), 3.76 (3H, s),3.76 (3H, s), 4.16-4.23 (1H, m), 5.03 (2H, brs), 5.18 (1H, d, J=17.1Hz), 5.22 (1H, d, J=16.6 Hz), 6.38-6.43 (2H, m), 6.57 (1H, dd, J=6.4,11.2 Hz), 7.10 (1H, d, J=4.9 Hz), 7.15-7.20 (2H, m), 7.71 (1H, dd,J=6.4, 10.3 Hz), 8.45 (1H, d, J=5.9 Hz), 8.59 (1H, d, J=4.9 Hz), 8.77(1H, s).

(82g)4-{[(1S*,2R*)-2-(3-Aminopyridazin-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-2-(3-aminopyridazin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(45 mg, 0.073 mmol) prepared in Example 82f, triethylsilane (0.06 mL),trifluoroacetic acid (0.08 mL) and dichloromethane (0.76 mL), to yieldthe title compound (25 mg, 74%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.48-1.60 (4H, m), 1.82-1.98 (3H, m),2.29-2.31 (1H, m), 3.06-3.11 (1H, m), 4.66-4.71 (1H, m), 6.96 (1H, dd,J=1.0, 6.4 Hz), 7.10 (1H, dd, J=6.4, 11.2 Hz), 7.36 (1H, d, J=4.9 Hz),7.65 (1H, dd, J=6.8, 10.3 Hz), 8.21 (1H, d, J=6.4 Hz), 8.28 (1H, d,J=4.9 Hz), 8.49 (1H, s).

MS (ESI) m/z: 463 [M+H]+.

Example 832,3-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(83a)N-(2,4-Dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(200 mg, 0.45 mmol) prepared in Example 30a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(110 mg, 0.45 mmol) prepared in Example 33b, sodium hydride (63%; 27 mg,0.680 mmol) and DMF (5.0 mL), to yield the title compound (80 mg, 26%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.36-1.66 (8H, m), 1.81-2.24 (6H, m),2.85-2.90 (1H, m), 3.62-3.67 (1H, m), 3.76 (3H, s), 3.79 (3H, s),3.98-4.01 (1H, m), 4.06-4.11 (1H, m), 5.24 (2H, s), 5.24-5.28 (1H, m),6.39-6.41 (2H, m), 6.60-6.64 (1H, m), 7.17-7.21 (2H, m), 7.43-7.46 (2H,m), 7.63 (1H, t, J=8.8 Hz), 8.44 (1H, d, J=6.4 Hz), 8.77 (1H, s).

(83b)2,3-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide(70 mg, 0.10 mmol) prepared in Example 83a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol(1.0 mL), to yield the title compound (15 mg, 33%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.33-1.79 (6H, m), 1.94-1.96 (1H, m),2.11-2.13 (1H, m), 2.77-2.82 (1H, m), 4.42 (1H, dt, J=3.9, 10.3 Hz),6.96 (1H, d, J=6.9 Hz), 7.10 (1H, t, J=8.3 Hz), 7.42 (2H, s), 7.56 (1H,t, J=8.8 Hz), 8.24 (1H, d, J=5.9 Hz), 8.55 (1H, s), 12.8 (1H, brs).

MS (ESI) m/z: 436 [M+H]+.

Example 844-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(84a)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(60 mg, 0.14 mmol) prepared in Example 65b, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (30 mg,0.14 mmol) prepared in Example 47b, sodium hydride (63%; 20 mg, 0.21mmol) and DMF (5.0 mL), to yield the title compound (51 mg, 59%) as acolorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90-2.17 (4H, m), 1.90 (3H, s),2.30-2.31 (1H, m), 2.73-2.80 (1H, m), 3.07-3.12 (1H, m), 3.77 (3H, s),3.79 (3H, s), 3.88 (3H, s), 4.51 (1H, dt, J=4.4, 10.7 Hz), 5.26 (2H, s),6.04 (1H, d, J=2.0 Hz), 6.39-6.42 (2H, m), 6.54 (1H, d, J=8.8 Hz), 7.20(1H, d, J=7.8 Hz), 7.25 (1H, dd, J=1.5, 5.9 Hz), 7.38 (1H, d, J=2.0 Hz),7.80 (1H, t, J=8.3 Hz), 8.42 (1H, d, J=5.9 Hz), 8.76 (1H, d, J=1.0 Hz).

(84b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(51 mg, 0.081 mmol) prepared in Example 84a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield thetitle compound (31 mg, 79%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90-2.12 (4H, m), 1.93 (3H, s),2.31-2.35 (1H, m), 2.73-2.78 (1H, m), 3.07-3.12 (1H, m), 3.89 (3H, s),4.50 (1H, dt, J=3.9, 10.7 Hz), 6.05 (1H, d, J=2.0 Hz), 6.55 (1H, d,J=8.8 Hz), 7.20 (1H, brs), 7.40 (1H, d, J=2.0 Hz), 7.76 (1H, t, J=8.8Hz), 8.42 (1H, brs), 8.78 (1H, brs).

MS (ESI) m/z: 482 [M+H]+.

Example 854-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclopentyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(85a)4-(Cyclopent-1-en-1-yl)-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 33a by using4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (WO2010/079443; 1.20 g, 4.35 mmol),2-cyclopent-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.20 g,6.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(250 mg, 0.342 mmol), potassium carbonate (2.00 g, 14.5 mmol) and DMF(13 mL), to yield the title compound (1.02 g, 89%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.63-1.73 (3H, m), 1.96-2.05 (4H, m),2.13-2.18 (1H, m), 2.51-2.55 (2H, m), 2.60-2.65 (2H, m), 3.69-3.74 (1H,m), 4.05-4.08 (1H, m), 5.41 (1H, dd, J=2.9, 8.8 Hz), 6.31-6.33 (1H, m),7.60 (1H, s).

(85b)(1S*,2R*)-2-[3-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the4-(cyclopent-1-en-1-yl)-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.02 g, 3.87 mmol) prepared in Example 85a, a borane-THF complex (0.95M solution in THF; 10 mL, 9.50 mmol), sodium perborate tetrahydrate(1.20 g, 7.80 mmol), THF (4.0 mL) and water (4.0 mL), to yield a mixtureof the title compound and a by-product.

(85c)N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.19 g, 0.43 mmol) prepared in Example 43a, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentanol(0.12 g, 0.43 mmol) prepared in Example 85b, sodium hydride (63%; 61 mg,0.64 mmol) and DMF (8.0 mL), to yield the title compound (129 mg, 43%)as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.66-2.05 (10H, m), 2.16 (3H, s),2.16-2.23 (1H, m), 2.34-2.35 (1H, m), 3.68-3.71 (1H, m), 3.76 (3H, s),3.79 (3H, s), 3.85-3.86 (1H, m), 4.04-4.06 (1H, m), 4.66-4.67 (1H, m),5.26 (2H, s), 5.38-5.40 (1H, m), 6.39-6.47 (3H, m), 7.20 (1H, d, J=7.8Hz), 7.30 (1H, d, J=5.9 Hz), 7.55 (1H, s), 7.72 (1H, d, J=7.8 Hz), 8.43(1H, d, J=5.9 Hz), 8.77 (1H, s).

(85d)2-Fluoro-5-methyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(101 mg, 0.185 mmol) prepared in Example 85c, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (65 mg, 76%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.70-1.99 (4H, m), 2.18 (3H, s),2.23-2.35 (3H, m), 3.83-3.86 (1H, m), 6.75 (1H, d, J=12.2 Hz), 7.10 (1H,d, J=6.4 Hz), 7.76 (1H, d, J=8.3 Hz), 7.80 (1H, s), 8.35 (1H, d, J=6.4Hz), 8.62 (1H, s).

(85e)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclopentyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 71c by using the2-fluoro-5-methyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(65 mg, 0.141 mmol) prepared in Example 85d, an iron powder (78.5 mg,1.41 mol), a saturated aqueous solution of ammonium chloride (1.0 mL)and ethanol (2.0 mL), to yield the title compound (30.6 mg, 50%) as acolorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.44-1.88 (5H, m), 1.98 (3H, s),2.20-2.22 (1H, m), 2.74-2.78 (1H, m), 4.38-4.42 (1H, m), 6.83 (1H, d,J=8.8 Hz), 7.06 (1H, d, J=7.3 Hz), 7.19 (1H, d, J=2.9 Hz), 7.75 (1H, t,J=8.8 Hz), 8.31 (1H, d, J=6.4 Hz), 8.56 (1H, s).

MS (ESI) m/z: 432 [M+H]+.

Example 865-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

(86a)5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (WO2010/079443; 5.00 g, 19.9 mmol) in THF (60 mL), lithiumbis(trimethylsilyl)amide (1.0 M solution in THF; 24.0 mL, 24.0 mmol) wasadded at −78° C. The reaction solution was stirred at room temperaturefor 10 minutes, and a solution of 5-chloro-2,4-difluorobenzenesulfonylchloride (5.41 g, 21.9 mmol) in THF (15 mL) was then added thereto at−78° C. The reaction solution was stirred at room temperature for 2hours, and water (100 mL) was then added to the reaction solution,followed by extraction with ethyl acetate (100 mL). The thus obtainedorganic layer was washed with saturated saline (100 mL) and dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=9:1) toyield the title compound (5.31 g, 58%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.70 (3H, s), 3.76 (3H, s), 5.33 (2H, s),6.26 (1H, d, J=2.4 Hz), 6.35 (1H, dd, J=2.4, 8.3 Hz), 6.96 (1H, t, J=8.3Hz), 7.25-7.26 (1H, m), 7.81 (1H, t, J=8.3 Hz), 8.84 (1H, s).

(86b)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(0.80 g, 1.73 mmol) prepared in Example 86a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.311 g, 1.73 mmol)prepared in Example 4a, sodium hydride (63%; 0.078 g, 2.05 mmol) and DMF(6.0 mL), to yield the title compound (0.466 g, 43%) as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-1.67 (4H, m), 1.87-1.98 (2H, m),2.05-2.08 (1H, m), 2.17-2.20 (1H, m), 3.02-3.07 (1H, m), 3.67 (3H, s),3.73 (3H, s), 3.93 (3H, s), 4.10-4.15 (1H, m), 5.25 (1H, d, J=15.1 Hz),5.31 (1H, d, J=15.1 Hz), 6.04 (1H, d, J=2.0 Hz), 6.24 (1H, d, J=2.4 Hz),6.33 (1H, dd, J=2.4, 5.9 Hz), 6.41 (1H, d, J=11.7 Hz), 7.23 (1H, d,J=8.8 Hz), 7.36 (1H, d, J=2.0 Hz), 7.68 (1H, d, J=7.3 Hz), 8.79 (1H, s).

(86c)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(0.466 g, 0.749 mmol) prepared in Example 86b, triethylsilane (0.50 mL),trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield thetitle compound (0.191 g, 54%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.43-1.64 (3H, m), 1.68-1.76 (1H, m),1.82-1.85 (1H, m), 1.90-1.92 (1H, m), 1.99-2.02 (1H, m), 2.22-2.24 (1H,m), 3.11-3.16 (1H, m), 3.88 (3H, s), 4.49 (1H, dt, J=3.9, 10.3 Hz), 6.16(1H, d, J=2.0 Hz), 6.95 (1H, d, J=11.7 Hz), 7.28 (1H, d, J=2.0 Hz), 7.75(1H, d, J=7.3 Hz), 8.54 (1H, s).

MS (ESI) m/z: 472 [M+H]+.

Example 875-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

(87a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(0.870 g, 1.88 mmol) prepared in Example 86a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.313 mg, 1.88mmol) prepared in Example 8a, sodium hydride (63%; 0.085 g, 2.23 mmol)and DMF (8.0 mL), to yield the title compound (0.377 g, 33%) as acolorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.80-1.98 (4H, m), 2.17-2.34 (2H, m),3.51 (1H, dt, J=4.9, 8.3 Hz), 3.72 (3H, s), 3.72 (3H, s), 3.89 (3H, s),4.59-4.62 (1H, m), 5.30 (2H, s), 6.06 (1H, d, J=2.0 Hz), 6.27 (1H, d,J=2.4 Hz), 6.34 (1H, dd, J=2.4, 8.8 Hz), 6.47 (1H, d, J=11.7 Hz), 7.25(1H, d, J=8.3 Hz), 7.41 (1H, d, J=2.0 Hz), 7.78 (1H, d, J=6.8 Hz), 8.80(1H, s).

(87b)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(0.377 g, 0.620 mmol) prepared in Example 87a, triethylsilane (0.50 mL),trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield thetitle compound (0.212 g, 75%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.79-1.98 (4H, m), 2.29-2.36 (2H, m),3.54 (1H, dt, J=5.9, 7.8 Hz), 3.84 (3H, s), 4.85-4.90 (1H, m), 6.21 (1H,d, J=2.0 Hz), 6.94 (1H, d, J=11.7 Hz), 7.37 (1H, d, J=2.0 Hz), 7.85 (1H,d, J=7.3 Hz), 8.55 (1H, s).

MS (ESI) m/z: 458 [M+H]+.

Example 884-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(88a) [(4,4-Difluorocyclohex-1-en-1-yl)oxy](trimethyl)silane

To a solution of N,N-diisopropylamine (3.30 g, 32.6 mmol) in THF (50mL), n-butyl lithium (1.65 M solution in hexane (18.0 mL, 29.7 mmol) wasadded dropwise with cooling on ice. The reaction solution was stirred at0° C. for 30 minutes. Then, 4,4-difluorocyclohexanone (3.60 g, 26.8mmol) was added thereto at −78° C., and the reaction solution wasstirred at −78° C. for 1 hour. To the reaction solution,chlorotrimethylsilane (4.4 mL, 34.8 mmol) and triethylamine (8.0 mL,57.4 mmol) were added, and the mixture was stirred at −78° C. for 2hours. To the reaction solution, a saturated aqueous solution of sodiumhydrogencarbonate (20 mL) was added, followed by extraction with ethylacetate (20 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=98:2) toyield the title compound (2.10 g, 56%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.20 (9H, s), 2.04-2.12 (2H, m),2.25-2.28 (2H, m), 2.50-2.56 (2H, m), 4.68-4.71 (1H, m).

(88b) 4,4-Difluorocyclohex-2-en-1-one

To a solution of the[(4,4-difluorocyclohex-1-en-1-yl)oxy](trimethyl)silane (3.1 g, 15.0mmol) prepared in Example 88a in acetonitrile (25 mL), palladium acetate(4.0 g, 17.8 mmol) was added, and the mixture was stirred at roomtemperature for 45 minutes. The reaction solution was filtered, thefiltrate was vacuum concentrated, and the residue was purified withsilica gel chromatography (hexane/ethyl acetate=9:1) to yield the titlecompound (1.0 g, 50%) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.47-2.56 (2H, m), 2.68 (2H, t, J=6.7Hz), 6.19 (1H, d, ¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.47-2.56 (2H, m), 2.68(2H, t, J=6.7 Hz), 6.19 (1H, d, J=10.6 Hz), 6.76-6.82 (1H, m).

(88c) 4,4-Difluoro-2-iodocyclohex-2-en-1-one

To a solution of the 4,4-difluorocyclohex-2-en-1-one (1.0 g, 7.57 mmol)prepared in Example 88b in a THF-water mixed solvent (1:1; 20 mL),potassium carbonate (1.30 g, 9.41 mmol), iodine (2.9 g, 11.4 mmol) andDMAP (0.56 g, 4.58 mmol) were added, and the reaction solution wasstirred at room temperature for 30 minutes. The reaction solution wassubjected to extraction with ethyl acetate (20 mL). The thus obtainedorganic layer was washed with an aqueous sodium thiosulfate solution (20mL) and dried over anhydrous sodium sulfate. After vacuum concentration,the residue was purified with silica gel chromatography (hexane/ethylacetate=9:1) to yield the title compound (1.46 g, 75%) as a light brownoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.51-2.59 (2H, m), 2.87 (2H, t, J=6.8Hz), 7.56-7.58 (1H, m).

(88d) 8,8-Difluoro-6-iodo-1,4-dioxaspiro[4.5]dec-6-ene

The reaction and aftertreatment were conducted in the same manner as inExample 67a by using the 4,4-difluoro-2-iodocyclohex-2-en-1-one (1.46 g,5.66 mmol) prepared in Example 88c, ethylene glycol (750 mg, 12.1 mmol),p-toluenesulfonic acid hydrate (60 mg, 0.31 mmol) and benzene (30 mL),to yield a mixture of the title compound and a by-product.

(88e)5-(8,8-Difluoro-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using the8,8-difluoro-6-iodo-1,4-dioxaspiro[4.5]dec-6-ene (1.34 g, 4.44 mmol)prepared in Example 88d,1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (1.40g, 6.73 mmol), tetrakis(triphenylphosphine)palladium (0) (250 mg, 0.216mmol), cesium carbonate (3.40 g, 10.4 mmol), dioxane (10 mL) and water(5.0 mL), to yield a mixture of the title compound and a by-product.

(88f) 4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one

The reaction and aftertreatment were conducted in the same manner as inExample 67c by using the5-(8,8-difluoro-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole(758 mg, 2.96 mmol) prepared in Example 88e, 5 M hydrochloric acid (10mL) and THF (10 mL), to yield the title compound (170 mg, 14%, 3 steps)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.59-2.57 (2H, m), 2.85 (2H, t, J=6.8Hz), 3.74 (3H, s), 6.29 (1H, d, J=2.0 Hz), 6.84 (1H, t, J=5.9 Hz), 7.48(1H, d, J=2.0 Hz).

(88g) (1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 67d by using the4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one (170 mg,0.80 mmol) prepared in Example 88f, sodium borohydride (60 mg, 1.59mmol), methanol (3.0 mL), palladium hydroxide carbon (10%; 150 mg) andethanol (4.0 mL), to yield the title compound (50 mg, 29%) as acolorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.80-2.00 (3H, m), 2.10-2.13 (1H, m),2.24-2.31 (2H, m), 2.98-3.03 (1H, m), 3.73 (1H, dt, J=4.4, 10.3 Hz),3.86 (3H, s), 6.08 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=2.0 Hz).

(88h)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(110 mg, 0.250 mmol) prepared in Example 14b, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (50 mg,0.231 mmol) prepared in Example 88g, sodium hydride (63%; 20 mg, 0.525mmol) and DMF (2.0 mL), to yield the title compound in a crude form as acolorless solid.

(88i)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the crude4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(150 mg, 0.236 mmol) prepared in Example 88h, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (98 mg, 80%, 2 steps) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.83-1.90 (1H, m), 2.19-2.38 (5H, m),3.43-3.48 (1H, m), 3.88 (3H, s), 4.62 (1H, dt, J=3.9, 6.4 Hz), 6.22 (1H,d, J=2.0 Hz), 6.97-7.01 (2H, m), 7.27 (1H, d, J=2.0 Hz), 7.69 (1H, dd,J=6.8, 10.7 Hz), 8.25 (1H, d, J=6.4 Hz), 8.54 (1H, s).

MS (ESI) m/z: 486 [M+H]+.

Example 894-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-3-ethyl-N-(pyrimidin-4-yl)benzenesulfonamide

(89a) 3-Ethyl-4-fluorobenzenesulfonyl chloride

The reaction and aftertreatment were conducted in the same manner as inExample 65a by using 1-ethyl-2-fluorobenzene (2.30 g, 19.0 mmol) andchlorosulfuric acid (4.9 mL, 74.0 mmol), to yield the title compound ina crude form.

(89b)N-(2,4-dimethoxybenzyl)-3-ethyl-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.80g, 3.30 mmol) prepared in Example 14a, the crude3-ethyl-4-fluorobenzenesulfonyl chloride (1.50 g, 6.50 mmol) prepared inExample 89a, 1,4-diazabicyclo[2.2.2]octane (0.73 g, 6.50 mmol) and THF(20 mL), to yield the title compound (1.35 g, 96%) as a colorless oil.

(89c)N-(2,4-dimethoxybenzyl)-3-ethyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-3-ethyl-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(1.50 g, 3.50 mmol) prepared in Example 89b, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(1.00 g, 3.50 mmol) prepared in Example 34b, sodium hydride (63%; 0.50g, 5.20 mmol) and DMF (30 mL), to yield the title compound (1.45 g, 59%)in the form of a diastereomeric mixture as a pale yellow solid.

(89d)3-Ethyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-3-ethyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(70 mg, 0.0990 mmol) prepared in Example 89c, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (47 mg, 99%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.92 (3H, t, J=7.3 Hz), 1.43-1.67 (4H,m), 1.81-1.91 (2H, m), 2.05-2.09 (1H, m), 2.27-2.30 (1H, m), 2.39 (2H,q, J=7.3 Hz), 3.58-3.63 (1H, m), 4.53-4.58 (1H, m), 7.03 (1H, d, J=8.8Hz), 7.19 (1H, d, J=6.4 Hz), 7.68-7.69 (2H, m), 7.78 (1H, dd, J=2.9, 8.8Hz), 8.42 (1H, d, J=6.4 Hz), 8.74 (1H, s).

(89e)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-3-ethyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 71c by using the3-ethyl-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(67 mg, 0.142 mmol) prepared in Example 89d, an iron powder (79 mg, 1.42mol), a saturated aqueous solution of ammonium chloride (1.0 mL) andethanol (2.0 mL), to yield the title compound (9.1 mg, 15%) as acolorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.03 (3H, t, J=7.8 Hz), 1.41-1.63 (4H,m), 1.77-1.86 (2H, m), 1.99-2.01 (1H, m), 2.20-2.23 (1H, m), 2.52-2.56(2H, m), 2.74-2.77 (1H, m), 4.37-4.41 (1H, m), 6.98 (1H, dd, J=2.4, 8.3Hz), 7.07-7.09 (1H, m), 7.16 (1H, d, J=2.4 Hz), 7.69 (1H, s), 7.73-7.75(1H, m), 8.32 (1H, dd, J=2.9, 6.4 Hz), 8.60 (1H, s).

MS (ESI) m/z: 443 [M+H]+.

Example 904-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(90a)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(180 mg, 0.413 mmol) prepared in Example 43a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (89 mg,0.413 mmol) prepared in Example 47b, sodium hydride (63%; 60 mg, 0.620mmol) and DMF (5.0 mL), to yield the title compound (172 mg, 66%) as acolorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.89-2.30 (5H, m), 2.05 (3H, s),2.67-2.74 (1H, m), 3.07-3.12 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.89(3H, s), 4.36 (1H, dt, J=4.9, 10.7 Hz), 5.23 (2H, s), 6.04 (1H, d, J=2.0Hz), 6.35-6.41 (3H, m), 7.19 (1H, d, J=8.3 Hz), 7.25 (1H, dd, J=1.0, 6.8Hz), 7.38 (1H, d, J=1.0 Hz), 7.70 (1H, d, J=7.8 Hz), 8.43 (1H, d, J=5.9Hz), 8.77 (1H, s).

(90b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(172 mg, 0.272 mmol) prepared in Example 90a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL) and dichloromethane (3.0 mL), to yield thetitle compound (131 mg, 99%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.91-2.33 (5H, m), 2.05 (3H, s),2.70-2.74 (1H, m), 3.07-3.12 (1H, m), 3.88 (3H, s), 4.38 (1H, dt, J=4.4,10.7 Hz), 6.05 (1H, d, J=2.0 Hz), 6.42 (1H, d, J=11.7 Hz), 6.15 (1H, d,J=5.9 Hz), 7.36 (1H, s), 7.71 (1H, d, J=8.3 Hz), 8.36 (1H, d, J=6.4 Hz),8.70 (1H, s).

MS (ESI) m/z: 482 [M+H]+.

Example 914-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-3-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(91a)3-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the3-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(239 mg, 0.525 mmol) prepared in Example 79a, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(155 mg, 0.525 mmol) prepared in Example 34b, sodium hydride (63%; 60.5mg, 0.630 mmol) and DMF (6.0 mL), to yield the title compound (249 mg,65%) in the form of a diastereomeric mixture as a colorless amorphoussolid.

(91b)3-Chloro-2-fluoro-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using the3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(198 mg, 0.341 mmol) prepared in Example 91a, triethylsilane (0.10 mL),trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (16 mg, 9.4%) as a pale yellowsolid.

¹H-NMR (500 MHz, CDCl₃) 5 ppm: 1.46-1.63 (4H, m), 1.79-2.09 (3H, m),2.31-2.35 (1H, m), 3.72-3.76 (1H, m), 4.23-4.30 (1H, m), 6.69 (1H, d,J=8.8 Hz), 7.48-7.52 (1H, m), 7.73-7.76 (2H, m), 8.43 (1H, d, J=6.9 Hz),8.92 (1H, s).

(91c)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-3-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 71c by using the3-chloro-2-fluoro-4-{(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(16 mg, 0.0322 mmol) prepared in Example 91b, an iron powder (18.0 mg,0.322 mol), a saturated aqueous solution of ammonium chloride (1.0 mL)and ethanol (2.0 mL), to yield the title compound (9.7 mg, 65%) as acolorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.42-1.56 (3H, m), 1.68-1.89 (3H, m),1.98-2.01 (1H, m), 2.15-2.20 (1H, m), 2.75-2.79 (1H, m), 4.44-4.49 (1H,m), 6.97-6.99 (2H, m), 7.30 (1H, brs), 7.82 (1H, t, J=8.3 Hz), 8.23 (1H,brs), 8.52 (1H, brs).

MS (ESI) m/z: 467 [M+H]+.

Example 922,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(92a) (1S*,2R*)-2-(1-Methyl-1H-1,2,3-triazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 8a by using 1-methyl-1H-1,2,3-triazole (2.00 g, 24.1 mmol),n-butyl lithium (2.69 M solution in hexane; 9.0 mL, 24.2 mmol),cyclohexene oxide (2.40 g, 24.5 mmol) and THF (70 mL), to yield thetitle compound (197 mg, 4.5%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.25-1.53 (4H, m), 1.78-1.89 (3H, m),2.11-2.12 (1H, m), 2.55-2.60 (1H, m), 3.55-3.60 (2H, m), 4.01 (3H, s),7.29 (1H, s).

(92b)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(240 mg, 0.546 mmol) prepared in Example 14b, the(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexanol (100 mg, 0.552mmol) prepared in Example 92a, sodium hydride (63%; 50 mg, 1.31 mmol)and DMF (3.0 mL), to yield the title compound (270 mg, 82%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41-1.54 (3H, m), 1.69-1.77 (1H, m),1.91-1.99 (2H, m), 2.09-2.12 (1H, m), 2.28-2.30 (1H, m), 3.01-3.06 (1H,m), 3.77 (3H, s), 3.78 (3H, s), 4.06-4.12 (1H, m), 4.12 (3H, s), 5.18(1H, d, J=17.1 Hz), 5.24 (1H, d, J=17.1 Hz), 6.39-6.41 (2H, m), 6.50(1H, dd, J=6.4, 10.7 Hz), 7.16 (1H, dd, J=1.5, 5.9 Hz), 7.18 (1H, d,J=8.8 Hz), 7.50 (1H, s), 7.71 (1H, dd, J=6.8, 10.3 Hz), 8.46 (1H, d,J=5.9 Hz), 8.79 (1H, s).

(92c)2,5-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(270 mg, 0.450 mmol) prepared in Example 92b, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (168 mg, 83%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.46-1.64 (3H, m), 1.73-1.92 (3H, m),2.02-2.05 (1H, m), 2.26-2.28 (1H, m), 3.16-3.21 (1H, m), 4.09 (3H, s),4.44 (1H, dt, J=3.9, 10.3 Hz), 6.98-7.02 (2H, m), 7.57 (1H, s), 7.68(1H, dd, J=6.4, 10.3 Hz), 8.25 (1H, d, J=6.4 Hz), 8.53 (1H, s).

MS (ESI) m/z: 451 [M+H]+.

Example 934-{[(1S*,2R*)-4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(93a) 6-Iodo-8,8-dimethyl-1,4-dioxaspiro[4.4]non-6-ene

The reaction and aftertreatment were conducted in the same manner as inExample 67a by using 2-iodo-4,4-dimethylcyclopent-2-en-1-one (U.S. Pat.No. 6,222,048; 3.77 g, 16.0 mmol), ethylene glycol (2.0 mL, 32.2 mmol),p-toluenesulfonic acid hydrate (100 mg, 0.526 mmol) and benzene (60 mL),to yield the title compound (3.30 g, 74%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.13 (6H, s), 1.95 (2H, s), 3.95-3.98(2H, m), 4.18-4.20 (2H, m), 6.23 (1H, s).

(93b)5-(8,8-Dimethyl-1,4-dioxaspiro[4.4]non-6-en-6-yl)-1-methyl-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using the6-iodo-8,8-dimethyl-1,4-dioxaspiro[4.4]non-6-ene (1.30 g, 4.64 mmol)prepared in Example 93a,1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (1.30g, 6.25 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200 mg, 0.245 mmol), cesium carbonate (3.30 g, 10.1 mmol), dioxane(10 mL) and water (5.0 mL), to yield the title compound (1.07 g, 98%) asan orange oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.23 (6H, s), 2.03 (2H, s), 3.77-3.79(2H, m), 3.85-3.90 (2H, m), 3.86 (3H, s), 5.95 (1H, s), 6.27 (1H, d,J=2.0 Hz), 7.43 (1H, d, J=2.0 Hz).

(93c) 4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-en-1-one

The reaction and aftertreatment were conducted in the same manner as inExample 67c by using the5-(8,8-dimethyl-1,4-dioxaspiro[4.4]non-6-en-6-yl)-1-methyl-1H-pyrazole(1.07 g, 4.56 mmol) prepared in Example 93b, 2 M hydrochloric acid (5.0mL) and THF (5.0 mL), to yield the title compound (780 mg, 90%) as alight brown solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.33 (6H, s), 2.46 (2H, s), 3.90 (3H, s),6.55 (1H, d, J=2.0 Hz), 7.47 (1H, d, J=2.0 Hz), 7.50 (1H, s).

(93d) 4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanone

A solution of the4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-en-1-one (780 mg,4.10 mmol) prepared in Example 93c and palladium carbon (5%; 700 mg) inethanol (8.0 mL) was stirred for 6 hours under a hydrogen atmosphere.The reaction solution was filtered through celite to yield the titlecompound (750 mg, 95%) in a crude form as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.19 (3H, s), 1.28 (3H, s), 2.02 (1H, t,J=12.2 Hz), 2.20-2.32 (3H, m), 3.68 (1H, dd, J=9.3, 12.2 Hz), 6.01 (1H,d, J=2.0 Hz), 7.40 (1H, d, J=2.0 Hz).

(93e) (1S*,2R*)-4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

To a solution of the4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanone (750 mg, 3.90mmol) prepared in Example 93d in methanol (8.0 mL), sodium borohydride(150 mg, 3.97 mmol) was added with cooling on ice, and the reactionsolution was stirred at room temperature for 1 hour. To the reactionsolution, water (50 mL) was added, followed by extraction with ethylacetate (100 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (dichloromethane/methanol=97:3)to yield the title compound (390 mg, 52%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.10 (3H, s), 1.18 (3H, s), 1.54 (1H, dd,J=11.2, 13.2 Hz), 1.59 (1H, dd, J=7.8, 12.7 Hz), 1.93 (1H, dd, J=7.8,12.7 Hz), 1.99 (1H, dd, J=7.8, 13.2 Hz), 3.11-3.16 (2H, m), 3.78 (3H,s), 4.21-4.27 (1H, m), 6.04 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=2.0 Hz).

(93f)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(290 mg, 0.660 mmol) prepared in Example 14b, the(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (130mg, 0.669 mmol) prepared in Example 93e, sodium hydride (63%; 60 mg,1.58 mmol) and DMF (3.0 mL), to yield the title compound (309 mg, 76%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.19 (3H, s), 1.24 (3H, s), 1.71-1.77(2H, m), 2.07 (1H, ddd, J=1.5, 7.8, 13.2 Hz), 2.14 (1H, dd, J=7.8, 13.7Hz), 3.69-3.75 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 3.88 (3H, s),4.58-4.62 (1H, m), 5.21 (1H, d, J=17.1 Hz), 5.25 (1H, d, J=17.1 Hz),6.08 (1H, d, J=2.0 Hz), 6.39-6.42 (2H, m), 6.47 (1H, dd, J=6.4, 10.7Hz), 7.17-7.20 (2H, m), 7.40 (1H, d, J=2.0 Hz), 7.75 (1H, dd, J=6.8,10.3 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, d, J=1.0 Hz).

(93g)4-{[(1S*,2R*)-4,4-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(309 mg, 0.504 mmol) prepared in Example 93f, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (212 mg, 91%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.18 (3H, s), 1.23 (3H, s), 1.69 (1H, dd,J=4.9, 13.7 Hz), 1.74 (1H, t, J=12.2 Hz), 2.07 (1H, dd, J=8.3, 13.2 Hz),2.24 (1H, dd, J=7.8, 13.7 Hz), 3.73-3.78 (1H, m), 3.81 (3H, s),4.83-4.91 (1H, m), 6.23 (1H, d, J=2.0 Hz), 6.88 (1H, dd, J=6.8, 11.7Hz), 7.03 (1H, d, J=6.4 Hz), 7.36 (1H, d, J=2.0 Hz), 7.75 (1H, dd,J=6.8, 10.3 Hz), 8.27 (1H, d, J=6.4 Hz), 8.56 (1H, s).

MS (ESI) m/z: 464 [M+H]+.

Example 942,6-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(94a)N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.45 mmol) prepared in Example 27a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(0.10 g, 0.40 mmol) prepared in Example 33b, sodium hydride (63%; 27 mg,0.68 mmol), DMF (6.0 mL) and water (0.008 mL), to yield the titlecompound (100 mg, 33%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.36-1.67 (8H, m), 1.80-2.17 (6H, m),2.77-2.82 (1H, m), 3.62-3.67 (1H, m), 3.77 (3H, s), 3.82 (3H, s),3.97-4.02 (2H, m), 5.26 (2H, s), 5.25-5.28 (1H, m), 6.37 (2H, dd, J=2.0,11.2 Hz), 6.41 (1H, dd, J=2.4, 8.3 Hz), 6.44 (1H, d, J=2.4 Hz), 7.18(1H, dt, J=1.5, 6.4 Hz), 7.21 (1H, d, J=8.3 Hz), 7.39 (2H, d, J=11.7Hz), 8.44 (1H, d, J=6.4 Hz), 8.78 (1H, s).

(94b)2,6-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide(100 mg, 0.171 mmol) prepared in Example 94a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol(1.0 mL), to yield the title compound (40 mg, 54%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.24-1.36 (2H, m), 1.44-1.59 (2H, m),1.68-1.75 (2H, m), 1.92-1.95 (1H, m), 2.07-2.09 (1H, m), 2.68-2.74 (1H,m), 4.36 (1H, dt, J=3.9, 10.3 Hz), 6.78 (2H, d, J=11.7 Hz), 6.95 (1H,brs), 7.42 (2H, s), 8.29 (1H, brs), 8.58 (1H, s).

MS (ESI) m/z: 436 [M+H]+

Example 954-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(2-²H)(pyrimidin-4-yl)benzenesulfonamide

(95a) N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine

A solution of 2,4-difluoropyrimidine (1.00 g, 8.62 mmol) and2,4-dimethoxybenzylamine (1.44 g, 8.62 mmol) in THF (28 mL) was stirredat room temperature for 1 hour. The reaction solution was vacuumconcentrated, and the residue was purified with silica gelchromatography to yield the title compound (2.27 g, 62%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.81 (3H, s), 3.83 (3H, s), 4.55 (2H,brs), 5.74 (1H, brs), 6.28 (1H, brs), 6.44 (1H, dd, J=2.4, 8.3 Hz), 6.48(1H, d, J=8.3 Hz), 7.23 (1H, brs), 7.92 (1H, brs).

(95b) N-(2,4-dimethoxybenzyl)(2-²H)pyrimidin-4-amine

To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine(0.700 g, 2.68 mmol) prepared in Example 95a in THF (9.0 mL), deuteratedlithium aluminum hydride (0.220 g, 5.35 mmol) was added, and thereaction solution was stirred at 40° C. for 1 hour. To the reactionsolution, water (10 mL) was added, the mixture was filtered throughcelite, and the filtrate was subjected to extraction with ethyl acetate(20 mL). The thus obtained organic layer was dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withsilica gel chromatography to yield the title compound (75 mg, 11%) as acolorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.82 (3H, s), 3.85 (3H, s), 4.45 (2H,brs), 5.56 (1H, brs), 6.36 (1H, d, J=5.9 Hz), 6.46 (1H, dd, J=2.4, 8.3Hz), 6.50 (1H, d, J=2.4 Hz), 7.20 (1H, d, J=7.8 Hz), 8.15 (1H, d, J=5.4Hz).

(95c)N-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(2-²H)(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 14b by using the N-(2,4-dimethoxybenzyl)(2-²H)pyrimidin-4-amine(100 mg, 0.39 mmol) prepared in Example 95b,2,3,4-trifluorobenzenesulfonyl chloride (180 mg, 0.77 mmol),1,4-diazabicyclo[2.2.2]octane (50 mg, 0.46 mmol) and THF (0.77 mL), toyield the title compound (68 mg, 40%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.80 (3H, s), 3.82 (3H, s), 5.27 (2H, s),6.44-6.46 (2H, m), 7.13-7.17 (2H, m), 7.24 (1H, d, J=7.8 Hz), 7.87-7.91(1H, m), 8.50 (1H, d, J=5.9 Hz).

(95d)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(2-²H)(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(2-²H)(pyrimidin-4-yl)benzenesulfonamide(68 mg, 0.15 mmol) prepared in Example 95c, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (30 mg, 0.17 mmol)prepared in Example 37a, sodium hydride (63%; 10 mg, 0.25 mmol), DMF(0.77 mL) and water (0.003 mL), to yield the title compound (59.2 mg,64%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41 (3H, t, J=7.3 Hz), 1.77-1.84 (2H,m), 1.94-2.00 (2H, m), 2.20-2.37 (2H, m), 3.48 (1H, dt, J=4.9, 8.38 Hz),3.78 (3H, s), 3.81 (3H, s), 4.12-4.25 (2H, m), 4.75-4.78 (1H, m), 5.25(1H, d, J=17.1 Hz), 5.30 (1H, d, J=17.1 Hz), 6.07 (1H, d, J=2.0 Hz),6.41-6.44 (2H, m), 6.66 (1H, t, J=8.8 Hz), 7.20-7.23 (2H, m), 7.46 (1H,d, J=2.0 Hz), 7.73 (1H, dt, J=2.0, 7.3 Hz), 8.46 (1H, d, J=5.9 Hz).

(95e)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(2-²H)(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(2-²H)(pyrimidin-4-yl)benzenesulfonamide(59.2 mg, 0.098 mmol) prepared in Example 95d, triethylsilane (0.080mL), trifluoroacetic acid (0.10 mL) and dichloromethane (1.0 mL), toyield the title compound (34.0 mg, 77%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.31 (3H, t, J=6.8 Hz), 1.78-1.97 (4H,m), 2.27-2.37 (2H, m), 3.52 (1H, dt, J=5.9, 8.3 Hz), 4.12-4.21 (2H, m),4.90-4.93 (1H, m), 6.20 (1H, d, J=2.0 Hz), 6.92 (1H, t, J=7.3 Hz), 7.20(1H, d, J=6.4 Hz), 7.41 (1H, d, J=2.0 Hz), 7.68-7.72 (1H, m), 8.24 (1H,d, J=6.8 Hz).

MS (ESI) m/z: 451 [M+H]+.

Example 96N-(4-{(1R*,2S*)-2-[5-fluoro-2-methyl-4-((pyrimidin-4-yl)sulfamoyl)phenoxy]cyclohexyl}-1H-pyrazol-3-yl)acetamide

(96a)4-({(1S*,2R*)-2-[3-Amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(193 mg, 0.272 mmol) prepared in Example 68a andbis(acetylacetonato)copper (II) (21.3 mg, 0.0815 mmol) in a mixedsolvent of THF (4.0 mL) and ethanol (4.0 mL), sodium borohydride (101mg, 2.66 mmol) was added, and the reaction solution was stirred at roomtemperature for 20 minutes. To the reaction solution, a saturatedaqueous solution of sodium hydrogencarbonate (10 mL) and ethyl acetate(10 mL) were added, the mixture was filtered through celite, and thefiltrate was subjected to extraction. The thus obtained organic layerwas dried over anhydrous sodium sulfate. After vacuum concentration, theresidue was purified with silica gel chromatography to yield the titlecompound (78 mg, 42%) as a light brown amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-2.15 (14H, m), 2.15 (3H, s),2.66-2.71 (1H, m), 3.59-3.62 (1H, m), 3.73 (2H, brs), 3.77 (3H, s), 3.78(3H, s), 4.00-4.03 (2H, m), 5.04 (1H, dt, J=2.0, 9.82 Hz), 5.25 (2H, s),6.39-6.44 (3H, m), 7.16 (1H, d, J=2.4 Hz), 7.20 (1H, d, J=7.8 Hz), 7.29(1H, dt, J=1.5, 5.9 Hz), 7.68 (1H, d, J=7.8 Hz), 8.43 (1H, d, J=6.4 Hz),8.77 (1H, s).

(96b) N-{4-[(1R*,2S*)-2-{4-[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)sulfamoyl]-5-fluoro-2-methylphenoxy}cyclohexyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl}acetamide

To a solution of the4-({(1S*,2R*)-2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(78 mg, 0.115 mmol) prepared in Example 96a in pyridine (0.50 mL),acetic anhydride (0.021 mL, 0.229 mmol) was added, and the reactionsolution was stirred at room temperature for 12 hours. To the reactionsolution, water (10 mL) and ethyl acetate (10 mL) were added, and theorganic layer was washed with water (10 mL) and then saturated saline(10 mL) and dried over anhydrous sodium sulfate. After vacuumconcentration, the residue was purified with silica gel chromatographyto yield the title compound (37.2 mg, 45%) as a colorless amorphoussolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38-2.16 (14H, m), 2.10 (3H, s), 2.16(3H, s), 2.73-2.93 (1H, m), 3.62 (2H, brs), 3.77 (3H, s), 3.78 (3H, s),3.93-4.01 (2H, m), 4.10-4.13 (1H, m), 5.17-5.20 (1H, m), 5.24 (2H, s),6.35-6.48 (3H, m), 7.18-7.20 (1H, m), 7.30-7.35 (2H, m), 7.67 (1H, d,J=6.8 Hz), 8.43 (1H, d, J=5.8 Hz), 8.77 (1H, s).

(96c)N-(4-{(1R*,2S*)-2-[5-fluoro-2-methyl-4-(pyrimidin-4-ylsulfamoyl)phenoxy]cyclohexyl}-1H-pyrazol-3-yl)acetamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-{4-[(1R*,2S*)-2-{4-[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)sulfamoyl]-5-fluoro-2-methylphenoxy}cyclohexyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl}acetamide(78 mg, 0.108 mmol) prepared in Example 96b, triethylsilane (0.10 mL),trifluoroacetic acid (0.50 mL), dichloromethane (2.0 mL) and methanol(1.0 mL), to yield the title compound (33.1 mg, 63%) as a colorlesssolid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.38-1.62 (4H, m), 1.76-1.86 (2H, m),2.04 (3H, s), 2.11-2.24 (2H, m), 2.14 (3H, s), 2.87-2.91 (1H, m), 4.38(1H, dt, J=3.9, 10.3 Hz), 6.78 (1H, d, J=12.7 Hz), 7.06 (1H, dd, J=1.0,6.8 Hz), 7.42 (1H, s), 7.67 (1H, d, J=8.3 Hz), 8.32 (1H, d, J=5.9 Hz),8.57 (1H, s).

MS (ESI) m/z: 489 [M+H]+.

Example 974-{[(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(97a)(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (2.40 g, 29.2 mmol), n-butyllithium (2.69 M solution in hexane; 10.9 mL, 29.3 mmol),(1R*,3S*,5S*)-3-benzyloxy-6-oxabicyclo[3.1.0]hexane (Tetrahedron, 2002,58, 4675-4689; 5.38 g, 28.3 mmol) and THF (90 mL), to yield the titlecompound (1.71 g, 22%) as a brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.81-1.87 (1H, m), 1.92-1.98 (1H, m),2.23-2.28 (1H, m), 2.55-2.60 (1H, m), 2.99-3.04 (1H, m), 3.88 (3H, s),4.17-4.22 (1H, m), 4.38-4.43 (1H, m), 4.50 (2H, s), 6.14 (1H, d, J=2.0Hz), 7.26-7.41 (6H, m).

(97b)4-{[(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(100 mg, 0.228 mmol) prepared in Example 14b, the(1S*,2R*,4R*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol(60 mg, 0.220 mmol) prepared in Example 97a, sodium hydride (63%; 40 mg,1.05 mmol) and DMF (2.0 mL), to yield the title compound (88 mg, 58%) asa colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.97-2.03 (1H, m), 2.06-2.14 (1H, m),2.38-2.43 (1H, m), 2.62-2.68 (1H, m), 3.46-3.51 (1H, m), 3.76 (3H, s),3.79 (3H, s), 3.86 (3H, s), 4.26-4.31 (1H, m), 4.52 (1H, d, J=11.7 Hz),4.57 (1H, d, J=11.7 Hz), 4.69-4.73 (1H, m), 5.20 (1H, d, J=17.1 Hz),5.24 (1H, d, J=17.1 Hz), 6.16 (1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.47(1H, dd, J=6.4, 11.2 Hz), 7.16 (1H, d, J=6.8 Hz), 7.20 (1H, d, J=7.8Hz), 7.30-7.42 (6H, m), 7.75 (1H, dd, J=6.4, 10.3 Hz), 8.45 (1H, d,J=5.9 Hz), 8.78 (1H, s).

(97c)4-{[(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R′,4R*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(88 mg, 0.127 mmol) prepared in Example 97b, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (60 mg, 87%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.90-1.96 (1H, m), 2.08-2.15 (1H, m),2.41-2.46 (1H, m), 2.64-2.70 (1H, m), 3.55-3.60 (1H, m), 3.79 (3H, s),4.29-4.33 (1H, m), 4.52 (1H, d, J=11.7 Hz), 4.55 (1H, d, J=11.7 Hz),4.93 (1H, q, J=6.8 Hz), 6.27 (1H, d, J=2.0 Hz), 6.88 (1H, dd, J=6.8,11.2 Hz), 7.03 (1H, dd, J=1.0, 6.4 Hz), 7.25-7.36 (6H, m), 7.74 (1H, dd,J=6.8, 10.3 Hz), 8.26 (1H, d, J=6.4 Hz), 8.55 (1H, s).

MS (ESI) m/z: 542 [M+H]+.

Example 984-{[(1S*,2R*,4S*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(98a)(1S*,2R*,4S*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (3.40 g, 41.4 mmol), n-butyllithium (2.69 M solution in hexane; 15.4 mL, 41.4 mmol),(1R*,3R*,5S*)-3-benzyloxy-6-oxabicyclo[3.1.0]hexane (Tetrahedron, 2002,58, 4675-4689; 7.77 g, 40.8 mmol) and THF (120 mL), to yield the titlecompound (2.58 g, 23%) as a brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.83-1.89 (1H, m), 2.01-2.05 (1H, m),2.14-2.19 (1H, m), 2.46-2.50 (1H, m), 2.73 (1H, d, J=8.3 Hz), 3.38-3.42(1H, m), 3.89 (3H, s), 4.11-4.15 (1H, m), 4.19-4.21 (1H, m), 4.54 (2H,s), 5.94 (1H, d, J=2.0 Hz), 7.29-7.41 (6H, m).

(98b)4-{[(1S*,2R*,4S*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(100 mg, 0.228 mmol) prepared in Example 14b, the(1S*,2R*,4S*)-4-benzyloxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (60mg, 0.220 mmol) prepared in Example 98a, sodium hydride (63%; 40 mg,1.05 mmol) and DMF (2.0 mL), to yield the title compound (143 mg, 94%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) 5 ppm: 1.92-1.99 (1H, m), 2.03-2.07 (1H, m),2.41-2.46 (1H, m), 2.57-2.63 (1H, m), 3.76 (3H, s), 3.79 (3H, s),3.86-3.90 (1H, m), 3.89 (3H, s), 4.18-4.20 (1H, m), 4.52 (2H, s),4.53-4.57 (1H, m), 5.21 (1H, d, J=17.1 Hz), 5.25 (1H, d, J=17.1 Hz),6.04 (1H, d, J=1.5 Hz), 6.39-6.42 (2H, m), 6.46 (1H, dd, J=6.4, 10.7Hz), 7.17-7.20 (2H, m), 7.28-7.38 (5H, m), 7.40 (1H, d, J=2.0 Hz), 7.76(1H, dd, J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(98c)4-{[(1S*,2R*,4S*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(143 mg, 0.207 mmol) prepared in Example 98b, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (91 mg, 81%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.94-2.03 (2H, m), 2.37-2.41 (1H, m),2.66-2.72 (1H, m), 3.81 (3H, s), 3.81-3.86 (1H, m), 4.20-4.22 (1H, m),4.51 (2H, s), 4.79-4.83 (1H, m), 6.20 (1H, d, J=1.5 Hz), 6.90 (1H, dd,J=6.4, 11.2 Hz), 7.03 (1H, d, J=6.4 Hz), 7.23-7.36 (6H, m), 7.76 (1H,dd, J=6.4, 10.3 Hz), 8.26 (1H, d, J=6.4 Hz), 8.55 (1H, s).

MS (ESI) m/z: 542 [M+H]+.

Example 994-{[(1S*,2R*)-3,3-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(99a) 2,2-Dimethyl-1-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 8a by using pyrazole (3.70 g, 45.1 mmol), n-butyl lithium (2.69M solution in hexane; 17 mL, 45.7 mmol), 2,2-dimethylcyclopentanone(5.00 g, 44.6 mmol) and THF (100 mL), to yield the title compound (630mg, 7.3%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.77 (3H, s), 1.14 (3H, s), 1.57-1.61(2H, m), 1.75-1.96 (4H, m), 2.53-2.59 (1H, m), 4.11 (3H, s), 6.07 (1H,d, J=2.0 Hz), 7.36 (1H, d, J=2.0 Hz).

(99b) 5-(5,5-Dimethylcyclopent-1-en-1-yl)-1-methyl-1H-pyrazole

A solution of the 2,2-dimethyl-1-(1-methyl-1H-pyrazol-5-yl)cyclopentanol(630 mg, 3.24 mmol) prepared in Example 99a and p-toluenesulfonic acidhydrate (2.00 g, 10.5 mmol) in toluene (20 mL) was stirred for 8 hoursunder reflux, and the solvent was subjected to azeotropic distillationwith water. After allowing to cool, water (50 mL) was added to thereaction solution, and an organic layer was extracted. The thus obtainedorganic layer was dried over anhydrous sodium sulfate. After vacuumconcentration, the residue was purified with silica gel chromatography(hexane/ethyl acetate=3:1) to yield the title compound (512 mg, 90%) asa brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.11 (6H, s), 1.86 (2H, t, J=6.8 Hz),2.47 (2H, dt, J=2.4, 7.3 Hz), 3.81 (3H, s), 5.73 (1H, t, J=2.4 Hz), 6.13(1H, d, J=2.0 Hz), 7.45 (1H, d, J=2.0 Hz).

(99c) (1S*,2R*)-3,3-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the5-(5,5-dimethylcyclopent-1-en-1-yl)-1-methyl-1H-pyrazole (500 mg, 2.84mmol) prepared in Example 99b, a borane-THF complex (0.95 M solution inTHF; 12.0 mL, 11.4 mmol), sodium perborate tetrahydrate (2.00 g, 13.0mmol), THF (2.0 mL) and water (6.0 mL), to yield the title compound (120mg, 22%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.76 (3H, s), 1.05 (3H, s), 1.60-1.86(3H, m), 2.18-2.25 (1H, m), 2.78 (1H, d, J=8.8 Hz), 2.81 (1H, brs), 3.78(3H, s), 4.44 (1H, dt, J=6.4, 8.8 Hz), 6.06 (1H, d, J=2.0 Hz), 7.39 (1H,d, J=2.0 Hz).

(99d)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-3,3-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(270 mg, 0.615 mmol) prepared in Example 14b, the(1S*,2R*)-3,3-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (120mg, 0.618 mmol) prepared in Example 99c, sodium hydride (63%; 40 mg,1.05 mmol) and DMF (3.0 mL), to yield the title compound (263 mg, 70%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.89 (3H, s), 1.13 (3H, s), 1.76-1.94(3H, m), 2.38-2.45 (1H, m), 3.24 (1H, d, J=6.8 Hz), 3.76 (3H, s), 3.79(3H, s), 3.87 (3H, s), 4.79-4.83 (1H, m), 5.20 (1H, d, J=17.1 Hz), 5.24(1H, d, J=17.1 Hz), 6.06 (1H, d, J=2.0 Hz), 6.39-6.41 (2H, m), 6.48 (1H,dd, J=6.4, 11.2 Hz), 7.17-7.20 (2H, m), 7.43 (1H, d, J=2.0 Hz), 7.71(1H, dd, J=6.4, 9.8 Hz), 8.45 (1H, d, J=5.9 Hz), 8.77 (1H, d, J=1.0 Hz).

(99e)4-{[(1S*,2R*)-3,3-Dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-3,3-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(263 Mg, 0.429 mmol) prepared in Example 99d, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (178 mg, 90%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.88 (3H, s), 1.11 (3H, s), 1.73-1.82(2H, m), 1.91-1.98 (1H, m), 2.48-2.56 (1H, m), 3.30-3.33 (1H, m), 3.82(3H, s), 5.10 (1H, dt, J=4.4, 7.8 Hz), 6.24 (1H, d, J=2.0 Hz), 6.94 (1H,dd, J=6.8, 11.7 Hz), 7.02 (1H, d, J=6.4 Hz), 7.39 (1H, d, J=2.0 Hz),7.70 (1H, dd, J=6.4, 10.3 Hz), 8.27 (1H, d, J=6.4 Hz), 8.54 (1H, s).

MS (FAB) m/z: 464 [M+H]+.

Example 1004-{[(1S*,2S*,3R*)-3-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(100a) (1R*,2R*,6S*)-7-Oxabicyclo[4.1.0]heptan-2-ol

To a solution of cyclohex-2-en-1-ol (14.9 g, 152 mmol) indichloromethane (200 mL), 3-chloroperbenzoic acid (70%; 42.0 g, 170mmol) was added with cooling on ice, and the reaction solution wasstirred for 1 hour with cooling on ice. To the reaction solution,saturated sodium thiosulfate (100 mL) and saturated sodiumhydrogencarbonate (100 mL) were added, and an organic layer wasextracted. The thus obtained organic layer was dried over anhydroussodium sulfate. After vacuum concentration, the residue was purifiedwith silica gel chromatography (hexane/ethyl acetate=2:3) to yield thetitle compound (3.10 g, 18%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.23-1.32 (1H, m), 1.43-1.59 (3H, m),1.76-1.91 (3H, m), 3.32 (1H, t, J=3.9 Hz), 3.35 (1H, t, J=3.9 Hz),3.99-4.04 (1H, m).

(100b) (1R*,2R*,6S*)-2-(Benzyloxy)-7-oxabicyclo[4.1.0]heptan-2-ol

To a solution of sodium hydride (63%; 1.20 g, 31.5 mmol) in THF (20 mL),a solution of the (1R*,2R*,6S*)-7-oxabicyclo[4.1.0]heptan-2-ol (3.10 g,27.2 mmol) prepared in Example 100a in THF (20 mL) was added withcooling on ice, and the mixture was stirred at room temperature for 1hour. To the reaction solution, benzyl bromide (4.0 mL, 33.4 mmol) wasadded, and the mixture was stirred at room temperature for 12 hours. Tothe reaction solution, water (50 mL) was added, followed by extractionwith ethyl acetate (50 mL). The thus obtained organic layer was driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography (hexane/ethyl acetate=4:1)to yield the title compound (2.85 g, 51%) as a light brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.18-1.25 (1H, m), 1.52-1.67 (3H, m),1.80-1.84 (2H, m), 3.26-3.27 (1H, m), 3.31-3.32 (1H, m), 3.79-3.81 (1H,m), 4.68 (1H, d, J=12.2 Hz), 4.71 (1H, d, J=12.2 Hz), 7.26-7.41 (5H, m).

(100c)(1S*,2R*,3R*)-3-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (2.30 g, 28.0 mmol), n-butyllithium (2.69 M solution in hexane; 10.0 mL, 26.9 mmol), the(1R*,2R*,6S*)-2-(benzyloxy)-7-oxabicyclo[4.1.0]heptan-2-ol (5.60 g, 27.4mmol) prepared in Example 100b and THF (80 mL), to yield the titlecompound (1.71 g, 22%) as a brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.32-1.45 (2H, m), 1.81-1.91 (2H, m),2.08-2.21 (2H, m), 2.75 (1H, t, J=10.3 Hz), 3.25-3.29 (1H, m), 3.73-3.78(1H, m), 3.85 (3H, s), 4.12 (1H, d, J=11.7 Hz), 4.37 (1H, d, J=11.7 Hz),6.10 (1H, d, J=2.0 Hz), 6.95 (1H, dd, J=1.5, 7.3 Hz), 7.22-7.26 (4H, m),7.51 (1H, d, J=2.0 Hz).

Also, a by-product(1R*,2S*,6R*)-2-(benzyloxy)-6-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(3.93 g, 50%) was obtained as a brown oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.35-1.47 (2H, m), 1.53-1.58 (1H, m),1.64-1.72 (1H, m), 1.86-1.90 (1H, m), 2.15-2.20 (1H, m), 2.38 (1H, d,J=8.8 Hz), 3.04-3.09 (1H, m), 3.58-3.62 (1H, m), 3.82 (3H, s), 3.89-3.91(1H, m), 4.53 (1H, d, J=11.7 Hz), 4.73 (1H, d, J=11.7 Hz), 6.07 (1H, d,J=2.0 Hz), 7.30-7.41 (6H, m).

(100d)4-{[(1S*,2S*,3R*)-3-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(200 mg, 0.455 mmol) prepared in Example 14b, the(1S*,2R*,3R*)-3-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(130 mg, 0.454 mmol) prepared in Example 100c, sodium hydride (63%; 50mg, 1.31 mmol) and DMF (3.0 mL), to yield the title compound (185 mg,58%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.36-1.57 (3H, m), 1.95-1.98 (1H, m),2.20-2.29 (2H, m), 3.11 (1H, t, J=10.3 Hz), 3.43-3.48 (1H, m), 3.76 (3H,s), 3.78 (3H, s), 3.89 (3H, s), 4.20 (1H, d, J=11.2 Hz), 4.21-4.26 (1H,m), 4.42 (1H, d, J=11.7 Hz), 5.21 (2H, s), 5.95 (1H, d, J=2.0 Hz),6.39-6.41 (2H, m), 6.48 (1H, dd, J=6.4, 11.2 Hz), 6.96-6.97 (2H, m),7.16-7.19 (2H, m), 7.23-7.26 (3H, m), 7.35 (1H, d, J=1.5 Hz), 7.66 (1H,dd, J=6.4, 9.8 Hz), 8.45 (1H, d, J=6.4 Hz), 8.78 (1H, d, J=1.0 Hz).

(100e)4-{[(1S*,2S*,3R*)-3-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2S*,3R*)-3-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(185 mg, 0.262 mmol) prepared in Example 100d, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (141 mg, 97%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.37-1.56 (3H, m), 1.91-1.94 (1H, m),2.23-2.33 (2H, m), 3.15 (1H, t, J=10.7 Hz), 3.57-3.62 (1H, m), 3.83 (3H,s), 4.18 (1H, d, J=11.2 Hz), 4.49 (1H, d, J=11.7 Hz), 4.58-4.63 (1H, m),6.15 (1H, d, J=2.0 Hz), 6.94-6.96 (2H, m), 7.01-7.05 (2H, m), 7.19-7.22(3H, m), 7.28 (1H, d, J=2.0 Hz), 7.64 (1H, dd, J=6.8, 10.3 Hz), 7.27(1H, d, J=6.4 Hz), 8.55 (1H, s).

MS (ESI) m/z: 556 [M+H]+.

Example 1012-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(101a) 4-(Cyclopent-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 39a by using 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J.Org. Chem., 2007, 72 (9), 3589-3591; 1.51 g, 5.42 mmol),2-cyclopent-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.37 g,7.05 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(317 mg, 0.434 mmol), cesium carbonate (6.01 g, 18.4 mmol), dioxane (27mL) and water (5.0 mL), to yield the title compound (1.00 g, 85%) as acolorless oil.

(101b)(1S*,2R*)-2-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the4-(cyclopent-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.00g, 4.60 mmol) prepared in Example 101a, a borane-THF complex (0.95 Msolution in THF; 10.6 mL, 10.1 mmol), sodium perborate tetrahydrate(1.49 g, 9.67 mmol), THF (5.0 mL) and water (10 mL), to yield the titlecompound (421 mg, 38%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.57-1.87 (6H, m), 2.03-2.15 (6H, m),2.81 (1H, q, J=7.3 Hz), 3.66-3.71 (1H, m), 4.01-4.07 (2H, m), 5.32 (1H,dd, J=2.0, 8.3 Hz), 7.44 (1H, s), 7.47 (1H, d, J=2.9 Hz).

(101c)N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.28 g, 0.63 mmol) prepared in Example 43a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentanol(0.15 g, 0.63 mmol) prepared in Example 101b, sodium hydride (63%; 91mg, 0.95 mmol) and DMF (6.4 mL), to yield the title compound (403 mg,97%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.57-1.92 (8H, m), 2.03-2.26 (4H, m),2.20 (3H, s), 3.25-3.30 (1H, m), 3.66-3.71 (1H, m), 3.76 (3H, s), 3.80(3H, s), 4.04-4.06 (1H, m), 4.46-4.50 (1H, m), 5.27 (2H, s), 5.30-5.34(1H, m), 6.39-6.45 (3H, m), 7.20 (1H, d, J=8.3 Hz), 7.31 (1H, dd, J=1.5,6.4 Hz), 7.43 (2H, d, J=2.9 Hz), 7.73 (1H, d, J=8.3 Hz), 8.43 (1H, d,J=6.4 Hz), 8.77 (1H, s).

(101d)2-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)benzenesulfonamide(0.12 g, 0.184 mmol) prepared in Example 101c, triethylsilane (0.10 mL),trifluoroacetic acid (0.50 mL), dichloromethane (1.0 mL) and methanol(1.0 mL), to yield the title compound (45 mg, 59%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm: 1.70-1.91 (4H, m), 2.19-2.27 (2H, m),2.20 (3H, s), 3.26-3.30 (1H, m), 4.64-4.68 (1H, m), 6.72 (1H, d, J=12.5Hz), 7.09 (1H, d, J=6.3 Hz), 7.51 (2H, s), 7.76 (1H, d, J=8.2 Hz), 8.32(1H, d, J=6.3 Hz), 8.59 (1H, s).

MS (ESI) m/z: 418 [M+H]+

Example 1024-{[(1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(102a)(1S,2R)-4,4-Difluoro-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol

To a solution of methanesulfonamide (480 mg, 5.05 mmol) in a mixedsolvent of t-butanol (10 mL) and water (10 mL), AD-mixα (Sigma-AldrichCorp.; 7.10 g) was added, and the reaction solution was stirred at roomtemperature for 10 minutes. To the reaction solution, a solution of the5-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-pyrazole (1.0 g, 5.05mmol) prepared in Example 47a in t-butanol (5 mL) was added with coolingon ice, and the reaction solution was vigorously stirred at roomtemperature for 16 hours. To the reaction solution, an aqueous sodiumsulfite solution (10 mL) was added, followed by extraction with ethylacetate (50 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate to yield the title compound in a crude form.

(102b)5-[(1S,6S)-4,4-Difluoro-7-oxabicyclo[4.1.0]hept-1-yl]-1-methyl-1H-pyrazole

A solution of the crude(1S,2R)-4,4-difluoro-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diolprepared in Example 102a, trimethyl orthoacetate (1.60 mL, 12.6 mmol)and p-toluenesulfonic acid (48 mg, 0.25 mmol) in dichloromethane (25 mL)was stirred for 45 hours. The reaction solution was concentrated anddiluted with acetonitrile (15 mL). Lithium bromide (220 mg, 2.53 mmol)and acetyl bromide (0.93 mL, 12.6 mmol) were added thereto with coolingon ice, and the reaction solution was stirred for 6 hours with coolingon ice. The reaction solution was concentrated and then diluted withmethanol (20 mL). Potassium carbonate (1.75 g, 12.7 mmol) was addedthereto, and the reaction solution was stirred at room temperature for 2hours. To the reaction solution, water (50 mL) was added, followed byextraction with ethyl acetate (100 mL). The thus obtained organic layerwas dried over anhydrous sodium sulfate. After vacuum concentration, theresidue was purified with silica gel chromatography to yield the titlecompound (752 mg, 70%, 2 steps) as a colorless solid.

(102c) (1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

A solution of the5-[(1S,6S)-4,4-difluoro-7-oxabicyclo[4.1.0]hept-1-yl]-1-methyl-1H-pyrazole(50 mg, 0.233 mmol) prepared in Example 102b and Raney nickel (500 mg)in isopropanol (20 mL) was stirred for 3 hours under a hydrogenatmosphere. The reaction solution was filtered, the filtrate wasconcentrated, and the residue was then purified with silica gelchromatography to yield the title compound (21.2 mg, 42%) as a colorlessoil.

(102d)4-{[(1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(145 mg, 0.33 mmol) prepared in Example 14b, the(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (50 mg,0.23 mmol) prepared in Example 102c, sodium hydride (63%; 12 mg, 0.33mmol), DMF (1.6 mL) and water (0.006 mL), to yield the title compound(130 mg, 62%) as a colorless oil.

(102e)4-{[(1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(130 mg, 0.20 mmol) prepared in Example 102d, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (70 mg, 99%) as a colorless solid.

[α]_(D) ²⁵=−7.62 (c 1.03, DMSO).

Example 1034-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(103a)4,4-Difluoro-1-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J.Org. Chem., 2007, 72 (9), 3589-3591; 10.0 g, 35.9 mmol),N,N,N′,N′-tetramethylethylenediamine (5.38 mL, 35.9 mmol), t-butyllithium (1.60 M solution in pentane; 26.2 mL, 43.2 mmol),4,4-difluorocyclohexanone (4.82 g, 35.9 mmol) and THF (100 mL), to yieldthe title compound (1.10 g, 11%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.61-1.75 (4H, m), 1.95-2.29 (10H, m),3.70 (1H, dt, J=2.9, 11.2 Hz), 4.06-4.09 (1H, m), 5.35 (1H, dd, J=3.4,8.8 Hz), 7.54 (1H, s), 7.59 (1H, s).

(103b)4-(4,4-Difluorocyclohex-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 99b by using the4,4-difluoro-1-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(1.10 g, 3.84 mmol) prepared in Example 103a, p-toluenesulfonic acid(0.33 g, 1.92 mmol) and toluene (20 mL), to yield the title compound(0.55 g, 70%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.61-1.72 (2H, m), 2.02-2.18 (6H, m),2.56-2.57 (2H, m), 2.65 (2H, t, J=14.7 Hz), 3.70 (1H, dt, J=2.4, 11.2Hz), 4.04-4.07 (1H, m), 5.35 (1H, dd, J=2.9, 9.3 Hz), 5.80-5.83 (1H, m),7.57 (1H, s), 7.61 (1H, s).

(103c)(1S*,2R*)-5,5-Difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the4-(4,4-difluorocyclohex-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(0.54 g, 2.01 mmol) prepared in Example 103b, a borane-THF complex (0.95M solution in THF; 4.70 mL, 4.42 mmol), sodium perborate tetrahydrate(0.61 g, 4.02 mmol), THF (20 mL) and water (20 mL), to yield the titlecompound (0.40 g, 70%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.57-2.20 (11H, m), 2.46-2.58 (2H, m),3.64-3.73 (2H, m), 4.06-4.09 (1H, m), 5.35 (1H, dd, J=2.9, 9.3 Hz), 7.49(1H, s), 7.53 (1H, s).

(103d)4-({(1S*,2R*)-5,5-Difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(184 mg, 0.42 mmol) prepared in Example 14b, the(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(100 mg, 0.35 mmol) prepared in Example 103c, sodium hydride (63%; 21mg, 0.52 mmol), DMF (5.0 mL) and water (0.0063 mL), to yield the titlecompound (180 mg, 75%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.57-1.67 (3H, m), 1.89-2.08 (6H, m),2.15-2.17 (1H, m), 2.24-2.28 (1H, m), 2.63-2.68 (1H, m), 2.93-2.98 (1H,m), 3.62-3.68 (1H, m), 3.77 (3H, s), 3.78 (3H, s), 4.00 (1H, d, J=10.7Hz), 4.16-4.22 (1H, m), 5.21 (2H, s), 5.25-5.30 (1H, m), 6.39-6.41 (2H,m), 6.48 (1H, dd, J=5.9, 10.7 Hz), 7.16-7.19 (2H, m), 7.46-7.48 (2H, m),7.73 (1H, dd, J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=2.4Hz).

(103e)4-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using the4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(170 mg, 0.24 mmol) prepared in Example 103d, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL), dichloromethane (2.0 mL) and methanol(2.0 mL), to yield the title compound (80 mg, 72%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.72-1.81 (1H, m), 1.97-2.20 (4H, m),2.59-2.63 (1H, m), 2.98-3.02 (1H, m), 4.63 (1H, dt, J=4.4, 10.7 Hz),6.96 (1H, brs), 7.14-7.18 (1H, m), 7.50 (2H, s), 7.62-7.65 (1H, m), 8.24(1H, brs), 8.57 (1H, s).

MS (ESI) m/z: 472 [M+H]+.

Example 1044-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(104a)4-({(1S*,2R*)-5,5-Difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(184 mg, 0.42 mmol) prepared in Example 27a, the(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(100 mg, 0.35 mmol) prepared in Example 103c, sodium hydride (63%; 20mg, 0.52 mmol), DMF (6.0 mL) and water (0.0060 mL), to yield the titlecompound (120 mg, 49%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.59-1.67 (3H, m), 1.86-2.04 (6H, m),2.14-2.17 (1H, m), 2.22-2.27 (1H, m), 2.64-2.65 (1H, m), 2.86-2.91 (1H,m), 3.63-3.68 (1H, m), 3.77 (3H, s), 3.82 (3H, s), 3.98-4.02 (1H, m),4.20-4.25 (1H, m), 5.25 (2H, s), 5.25-5.29 (1H, m), 6.36-6.44 (4H, m),7.14-7.16 (1H, m), 7.21 (1H, d, J=8.3 Hz), 7.41-7.42 (2H, m), 8.44 (1H,d, J=5.9 Hz), 8.78 (1H, s).

(104b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using the4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(120 mg, 0.24 mmol) prepared in Example 104a, triethylsilane (0.15 mL),trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol(1.5 mL), to yield the title compound (45 mg, 56%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.75-1.80 (1H, m), 1.97-2.13 (4H, m),2.55-2.57 (1H, m), 2.91-2.96 (1H, m), 4.58 (1H, dt, J=4.4, 10.3 Hz),6.75 (2H, d, J=11.2 Hz), 6.89-6.99 (1H, m), 7.44 (1H, brs), 7.51 (1H,s), 8.28 (1H, s), 8.58 (1H, s).

MS (ESI) m/z: 472 [M+H]+.

Example 1054-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(105a)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(145 mg, 0.33 mmol) prepared in Example 30a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (50 mg,0.23 mmol) prepared in Example 47b, sodium hydride (63%; 12.6 mg, 0.33mmol), DMF (1.6 mL) and water (0.0059 mL), to yield the title compound(113 mg, 62%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.92-2.13 (4H, m), 2.30-2.35 (1H, m),2.73-2.79 (1H, m), 3.08-3.13 (1H, m), 3.77 (6H, s), 3.91 (3H, s), 4.43(1H, dt, J=4.9, 11.2 Hz), 5.20 (1H, d, J=16.6 Hz), 5.25 (1H, dd, J=16.6Hz), 6.08 (1H, d, J=2.4 Hz), 6.40-6.41 (2H, m), 6.55-6.58 (1H, m),7.17-7.20 (2H, m), 7.37 (1H, d, J=2.0 Hz), 7.64-7.68 (1H, m), 8.45 (1H,d, J=6.4 Hz), 8.77 (1H, s).

(105b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(130 mg, 0.20 mmol) prepared in Example 105a, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (80 mg, 81%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.93-2.27 (5H, m), 2.72-2.76 (1H, m),3.35-3.41 (1H, m), 3.89 (3H, s), 4.68 (1H, dt, J=4.9, 10.7 Hz), 6.23(1H, d, J=2.0 Hz), 6.92 (1H, t, J=7.3 Hz), 7.09 (1H, d, J=6.8 Hz), 7.32(1H, d, J=2.0 Hz), 7.68-7.72 (1H, m), 7.33 (1H, d, J=6.8 Hz), 8.63 (1H,brs).

MS (ESI) m/z: 486 [M+H]+.

Example 1062,5-Difluoro-4-{[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(106a)5-[(1R*,2S*,4S*)-4-(Benzyloxy)-2-(methoxymethoxy)cyclopentyl]-1-methyl-1H-pyrazole

To a solution of the(1S*,2R*,4S*)-4-benzyloxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (350mg, 1.29 mmol) prepared in Example 98a and diisopropylethylamine (1.3mL, 7.64 mmol) in dichloromethane (5.0 mL), chloromethyl methyl ether(0.48 mL, 6.32 mmol) was added, and the reaction solution was stirred at40° C. for 5 hours. After allowing to cool, water (10 mL) was added tothe reaction solution, and an organic layer was extracted. The thusobtained organic layer was dried over anhydrous sodium sulfate. Aftervacuum concentration, the residue was purified with silica gelchromatography (hexane/ethyl acetate=1:2) to yield the title compound(250 mg, 62%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.81-1.91 (2H, m), 2.25-2.29 (1H, m),2.49-2.53 (1H, m), 3.22 (3H, s), 3.42-3.47 (1H, m), 3.87 (3H, s),4.00-4.05 (1H, m), 4.05-4.10 (1H, m), 4.49-4.55 (3H, m), 4.61 (1H, d,J=6.8 Hz), 6.03 (1H, d, J=2.0 Hz), 7.28-7.36 (5H, m), 7.39 (1H, d, J=1.5Hz).

(106b)(1S*,3R*,4S*)-3-(Methoxymethoxy)-4-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

A solution of the5-[(1R*,2S*,4S*)-4-(benzyloxy)-2-(methoxymethoxy)cyclopentyl]-1-methyl-1H-pyrazole(250 mg, 0.790 mmol) prepared in Example 106a and palladium carbon (5%;200 mg) in ethanol (3.0 mL) was stirred for 5 hours under a hydrogenatmosphere. The reaction solution was filtered through celite, thefiltrate was concentrated, and the residue was purified with silica gelchromatography (dichloromethane/methanol=96:4) to yield the titlecompound (150 mg, 84%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.84-1.88 (1H, m), 1.93-1.99 (1H, m),2.21-2.26 (1H, m), 2.32-2.38 (1H, m), 2.48 (1H, brs), 3.28 (3H, s),3.53-3.57 (1H, m), 3.89 (3H, s), 4.10-4.13 (1H, m), 4.46 (1H, brs), 4.59(1H, d, J=6.8 Hz), 4.65 (1H, d, J=6.8 Hz), 5.99 (1H, d, J=2.0 Hz), 7.39(1H, d, J=2.0 Hz).

(106c)5-[(1R*,2S*,4S*)-4-Fluoro-2-(methoxymethoxy)cyclopentyl]-1-methyl-1H-pyrazole

To a solution of the(1S*,3R*,4S*)-3-(methoxymethoxy)-4-(1-methyl-1H-pyrazol-5-yl)cyclopentanol(150 mg, 0.663 mmol) prepared in Example 106b in dichloromethane (2.0mL), bis(2-methoxyethyl)amino sulfur trifluoride (0.26 mL, 1.33 mmol)was added with cooling on ice, and the reaction solution was stirred atroom temperature for 2 hours. To the reaction solution, an aqueoussodium hydrogencarbonate solution (10 mL) was added, and an organiclayer was extracted. The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=2:3) toyield the title compound (132 mg, 87%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.88-2.08 (2H, m), 2.41-2.50 (1H, m),2.60-2.71 (1H, m), 3.18-3.23 (1H, m), 3.23 (3H, s), 3.87 (3H, s),4.26-4.32 (1H, m), 4.55 (1H, d, J=6.8 Hz), 4.60 (1H, d, J=6.8 Hz),5.17-5.31 (1H, m), 6.17 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=2.0 Hz).

(106d)5-[(1S*,2R*,4R*)-4-Fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

A solution of the5-[(1R*,2S*,4S*)-4-fluoro-2-(methoxymethoxy)cyclopentyl]-1-methyl-1H-pyrazole(132 mg, 0.579 mmol) prepared in Example 106c in 2 M hydrochloricacid-methanol (3.0 mL) was stirred at room temperature for 1 hour. Tothe reaction solution, an aqueous sodium hydrogencarbonate solution (10mL) was added, and an organic layer was extracted with ethyl acetate (10mL). The thus obtained organic layer was dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withreverse phase chromatography (30% methanol/water) to yield the titlecompound (90 mg, 85%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.87-2.06 (2H, m), 2.36-2.45 (1H, m),2.62-2.74 (1H, m), 3.04 (1H, q, J=8.8 Hz), 3.37 (1H, brs), 3.74 (3H, s),4.42-4.46 (1H, m), 5.14-5.27 (1H, m), 6.12 (1H, d, J=2.0 Hz), 7.32 (1H,d, J=2.0 Hz).

(106e)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(215 mg, 0.489 mmol) prepared in Example 14b, the5-[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (90mg, 0.489 mmol) prepared in Example 106d, sodium hydride (63%; 50 mg,1.31 mmol) and DMF (3.0 mL), to yield the title compound (235 mg, 80%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.07-2.26 (2H, m), 2.62-2.84 (2H, m),3.53-3.58 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 3.85 (3H, s), 4.83 (1H,q, J=6.8 Hz), 5.20 (1H, d, J=17.1 Hz), 5.24 (1H, d, J=17.1 Hz),5.27-5.40 (1H, m), 6.19 (1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.52 (1H,dd, J=6.4, 10.7 Hz), 7.15 (1H, d, J=1.0, 5.9 Hz), 7.20 (1H, d, J=8.8Hz), 7.42 (1H, d, J=2.0 Hz), 7.77 (1H, dd, J=6.4, 9.8 Hz), 8.45 (1H, d,J=5.9 Hz), 8.78 (1H, s).

(106f)2,5-Difluoro-4-{[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(235 mg, 0.389 mmol) prepared in Example 106e, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (162 mg, 92%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.90-2.18 (2H, m), 2.58-2.79 (2H, m),3.62 (1H, q, J=8.8 Hz), 3.75 (3H, s), 5.13 (1H, q, J=6.9 Hz), 5.27-5.42(1H, m), 6.24 (1H, d, J=2.4 Hz), 6.96 (1H, brs), 7.21-7.23 (1H, m), 7.31(1H, d, J=2.0 Hz), 7.68-7.72 (1H, m), 8.24 (1H, brs), 8.58 (1H, s).

MS (ESI) m/z: 454 [M+H]+.

Example 1074-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(107a)(1S*,2R*,4S*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentylbenzoate

To a solution of the(1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol(234 mg, 0.859 mmol) prepared in Example 98a and triethylamine (0.40 mL,2.87 mmol) in dichloromethane (4.0 mL), benzoyl chloride (0.260 mL, 2.24mmol) was added, and the reaction solution was stirred for 5 hours. Tothe reaction solution, water (50 mL) was added, and an organic layer wasextracted. The thus obtained organic layer was dried over anhydroussodium sulfate. After vacuum concentration, the residue was purifiedwith column chromatography (hexane/ethyl acetate=3:2) to yield the titlecompound (297 mg, 92%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.97-2.08 (2H, m), 2.41-2.46 (1H, m),2.62-2.68 (1H, m), 3.72-3.77 (1H, m), 3.89 (3H, s), 4.22-4.25 (1H, m),4.51 (1H, d, J=11.7 Hz), 4.56 (1H, d, J=11.7 Hz), 5.33 (1H, dt, J=4.9,7.3 Hz), 6.06 (1H, d, J=1.5 Hz), 7.28-7.44 (8H, m), 7.54-7.58 (1H, m),8.02 (2H, d, J=8.3 Hz).

(107b) (1S*,2R*,4S*)-4-Hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 106b by using the(1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentylbenzoate (297 mg, 0.789 mmol) prepared in Example 107a, palladium carbon(5%; 300 mg) and ethanol (3.0 mL), to yield the title compound (205 mg,91%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.88-1.92 (1H, m), 2.03-2.09 (1H, m),2.28-2.33 (1H, m), 2.66-2.71 (1H, m), 3.79-3.84 (1H, m), 3.91 (3H, s),4.58-4.60 (1H, m), 5.31-5.35 (1H, m), 6.06 (1H, d, J=2.0 Hz), 7.39 (1H,d, J=2.0 Hz), 7.43-7.46 (2H, m), 7.56-7.59 (1H, m), 8.01-8.03 (2H, m).

(107c) (1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)-4-oxocyclopentyl benzoate

To a solution of the(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl benzoate(205 mg, 0.716 mmol) prepared in Example 107b in dichloromethane (3.0mL), a Dess-Martin reagent (610 mg, 1.44 mmol) was added, and thereaction solution was stirred for 2 hours. To the reaction solution, anaqueous sodium hydrogencarbonate solution (10 mL) was added, and anorganic layer was extracted with dichloromethane (10 mL). The thusobtained organic layer was dried over anhydrous sodium sulfate. Aftervacuum concentration, the residue was purified with silica gelchromatography (hexane/ethyl acetate=2:3) to yield the title compound(140 mg, 69%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.47-2.59 (2H, m), 2.81-2.98 (2H, m),3.88-3.89 (1H, m), 4.09 (3H, s), 5.57-5.59 (1H, m), 6.03 (1H, d, J=2.0Hz), 7.43-7.49 (3H, m), 7.60-7.63 (1H, m), 8.02-8.04 (2H, m).

(107d) (1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 106c by using the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)-4-oxocyclopentyl benzoate (140mg, 0.716 mmol) prepared in Example 107c, bis(2-methoxyethyl)aminosulfur trifluoride (0.80 mL, 4.10 mmol) and dichloromethane (3.0 mL), toyield the title compound (90 mg, 60%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.35-2.47 (2H, m), 2.76-2.93 (2H, m),3.68-3.72 (1H, m), 3.97 (3H, s), 5.38-5.41 (1H, m), 6.19 (1H, d, J=2.0Hz), 7.43-7.48 (3H, m), 7.58-7.62 (1H, m), 8.01-8.03 (2H, m).

(107e) (1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

To a solution of the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl benzoate(90 mg, 0.294 mmol) prepared in Example 107d in methanol (3.0 mL),potassium carbonate (60 mg, 0.434 mmol) was added, and the reactionsolution was stirred for 30 minutes. To the reaction solution, water (10mL) was added, and an organic layer was extracted with ethyl acetate (20mL). The thus obtained organic layer was dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withsilica gel chromatography (dichloromethane/methanol=96:4) to yield thetitle compound (48 mg, 81%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.14-2.38 (2H, m), 2.60-2.71 (2H, m),3.24-3.30 (1H, m), 3.68 (1H, brs), 3.79 (3H, s), 4.26-4.31 (1H, m), 6.08(1H, d, J=1.5 Hz), 7.33 (1H, d, J=1.5 Hz).

(107f)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(105 mg, 0.239 mmol) prepared in Example 14b, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (48 mg,0.237 mmol) prepared in Example 107e, sodium hydride (63%; 30 mg, 0.788mmol) and DMF (2.0 mL), to yield the title compound (118 mg, 79%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.33-2.45 (2H, m), 2.74-2.92 (2H, m),3.75-3.80 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 3.90 (3H, s), 4.67 (1H,q, J=6.8 Hz), 5.20 (1H, d, J=16.6 Hz), 5.24 (1H, d, J=16.6 Hz), 6.14(1H, d, J=2.0 Hz), 6.39-6.47 (3H, m), 7.15 (1H, dd, J=1.5, 5.9 Hz), 7.19(1H, d, J=8.3 Hz), 7.43 (1H, d, J=2.0 Hz), 7.79 (1H, dd, J=6.8, 10.3Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=1.0 Hz).

(107g)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(118 mg, 0.190 mmol) prepared in Example 107f, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (50 mg, 56%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 2.29-2.43 (2H, m), 2.73-2.80 (1H, m),2.99-3.01 (1H, m), 3.79-3.84 (1H, m), 3.79 (3H, s), 5.04-5.08 (1H, m),6.29 (1H, s), 6.98 (1H, brs), 7.20-7.23 (1H, m), 7.33 (1H, s), 7.71 (1H,brs), 8.21 (1H, brs), 8.57 (1H, s).

MS (ESI) m/z: 472 [M+H]+.

Example 1082-Fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(108a)N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.303 g, 0.719 mmol) prepared in Example 29a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(0.15 g, 0.599 mmol) prepared in Example 33b, sodium hydride (63%; 35mg, 0.898 mmol), DMF (5.0 mL) and water (0.010 mL), to yield the titlecompound (0.14 g, 35%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.37-1.69 (8H, m), 1.80-2.20 (6H, m),2.79-2.83 (1H, m), 3.62-3.67 (1H, m), 3.77 (3H, s), 3.80 (3H, s),3.97-4.06 (2H, m), 5.25 (2H, s), 5.25-5.27 (1H, m), 6.39-6.43 (2H, m),6.50 (1H, dt, J=2.4, 12.2 Hz), 6.64-6.67 (1H, m), 7.20 (1H, d, J=8.3Hz), 7.24 (1H, dt, J=2.0, 5.9 Hz), 7.38 (1H, d, J=2.0 Hz), 7.42 (1H, s),7.88 (1H, dt, J=1.0, 8.3 Hz), 8.42 (1H, d, J=5.9 Hz), 8.76 (1H, s).

(108b)2-Fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using theN-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide(0.12 g, 0.171 mmol) prepared in Example 108a, triethylsilane (0.15 mL),trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol(1.5 mL), to yield the title compound (60 mg, 76%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.24-1.38 (2H, m), 1.44-1.60 (2H, m),1.69-1.76 (2H, m), 1.91-1.96 (1H, m), 2.09-2.12 (1H, m), 2.71-2.76 (1H,m), 4.34 (1H, dt, J=3.9, 10.3 Hz), 6.84 (1H, dd, J=2.0, 8.8 Hz), 6.94(1H, d, J=12.2 Hz), 6.99 (1H, brs), 7.42 (2H, s), 7.76 (1H, t, J=8.8Hz), 8.30 (1H, brs), 8.57 (1H, s).

MS (ESI) m/z: 418 [M+H]+.

Example 1094-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(109a)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(243 mg, 0.55 mmol) prepared in Example 27a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (100 mg,0.46 mmol) prepared in Example 47b, sodium hydride (63%; 27 mg, 0.69mmol), DMF (4.0 mL) and water (0.008 mL), to yield the title compound(140 mg, 48%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90-2.11 (4H, m), 2.29-2.33 (1H, m),2.69-2.74 (1H, m), 3.00-3.05 (1H, m), 3.77 (3H, s), 3.81 (3H, s), 3.87(3H, s), 4.36 (1H, dt, J=4.4, 10.7 Hz), 5.24 (2H, s), 6.05 (1H, d, J=2.0Hz), 6.30 (2H, d, J=10.7 Hz), 6.40-6.44 (2H, m), 7.13 (1H, dd, J=1.5,5.9 Hz), 7.21 (1H, d, J=8.3 Hz), 7.37 (1H, d, J=2.0 Hz), 8.45 (1H, d,J=5.8 Hz), 8.78 (1H, d, J=1.0 Hz).

(109b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(120 mg, 0.188 mmol) prepared in Example 109a, triethylsilane (0.15 mL),trifluoroacetic acid (1.5 mL) and dichloromethane (1.5 mL), to yield thetitle compound (45 mg, 49%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.24-1.29 (1H, m), 1.67-1.76 (1H, m),1.91-2.22 (3H, m), 2.64-2.66 (1H, m), 3.27-3.33 (1H, m), 3.77 (3H, s),4.70 (1H, dt, J=4.4, 10.3 Hz), 6.19 (1H, d, J=2.0 Hz), 6.70-6.73 (2H,m), 6.91 (1H, brs), 7.20 (1H, d, J=2.0 Hz), 8.27 (1H, brs), 8.57 (1H,s).

MS (ESI) m/z: 486 [M+H]+.

Example 1104-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(110a)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.23 g, 0.55 mmol) prepared in Example 29a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.10 g,0.46 mmol) prepared in Example 47b, sodium hydride (63%; 27 mg, 0.69mmol), DMF (4.0 mL) and water (0.008 mL), to yield the title compound(0.18 g, 64%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90-2.11 (4H, m), 2.26-2.32 (1H, m),2.70-2.75 (1H, m), 3.01-3.06 (1H, m), 3.77 (3H, s), 3.78 (3H, s), 3.89(3H, s), 4.40 (1H, dt, J=4.4, 10.3 Hz), 5.23 (2H, s), 6.05 (1H, d, J=2.0Hz), 6.39-6.45 (3H, m), 6.59 (1H, dd, J=2.4, 8.8 Hz), 7.18-7.20 (2H, m),7.36 (1H, d, J=2.0 Hz), 7.89 (1H, t, J=8.3 Hz), 7.43 (1H, d, J=5.9 Hz),8.76 (1H, s).

(110b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.18 g, 0.29 mmol) prepared in Example 110a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (100 mg, 73%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.68-1.77 (1H, m), 1.96-2.24 (4H, m),2.62-2.67 (1H, m), 3.30-3.35 (1H, m), 3.80 (3H, s), 4.64 (1H, dt, J=4.4,10.3 Hz), 6.17 (1H, d, J=1.5 Hz), 6.79 (1H, dd, J=2.4, 8.8 Hz), 6.85(1H, dd, J=2.4, 12.2 Hz), 6.96 (1H, brs), 7.20 (1H, d, J=2.0 Hz), 7.76(1H, t, J=8.3 Hz), 8.29 (1H, brs), 8.57 (1H, s).

MS (ESI) m/z: 468 [M+H]+.

Example 1112,6-Difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

(111a) t-Butyl(2,4-dimethoxybenzyl)[(2,4,6-trifluorophenyl)sulfonyl]carbamate

To a solution of 2,4-dimethoxybenzylamine (0.45 mL, 2.99 mmol) andpyridine (1.21 mL, 15.0 mmol) in dichloromethane (15 mL),2,4,6-trifluorobenzenesulfonyl chloride (0.69 g, 2.99 mmol) was added at0° C., and the mixture was stirred at room temperature for 1 hour. Tothe reaction solution, di-tert-butyl dicarbonate (2.94 g, 13.5 mmol) anddimethylaminopyridine (0.15 g, 1.20 mmol) were added, and the mixturewas stirred at room temperature for 6 hours. Water (50 mL) was addedthereto, and an organic layer was extracted. The thus obtained organiclayer was dried over anhydrous sodium sulfate and vacuum concentrated toyield the title compound (0.783 g, 57%) as a colorless amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.31 (9H, s), 3.79 (3H, s), 3.81 (3H, s),4.98 (2H, s), 6.44 (1H, d, J=2.4 Hz), 6.47 (1H, dd, J=2.4, 8.2 Hz), 6.80(2H, t, J=8.2 Hz), 7.23 (1H, d, J=8.2 Hz).

(111b) t-Butyl[(2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the t-butyl(2,4-dimethoxybenzyl)[(2,4,6-trifluorophenyl)sulfonyl]carbamate (0.78 g,1.70 mmol) prepared in Example 111a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.31 g, 1.70 mmol)prepared in Example 8a, sodium hydride (63%; 0.08 g, 2.04 mmol), DMF(8.5 mL) and water (0.05 mL), to yield the title compound (740.3 mg,70%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.31 (9H, s), 1.73-1.96 (4H, m),2.20-2.32 (2H, m), 3.37-3.41 (1H, m), 3.79 (3H, s), 3.81 (3H, s), 3.84(3H, s), 4.66-4.69 (1H, m), 4.97 (2H, s), 6.06 (1H, d, J=2.0 Hz),6.42-6.49 (4H, m), 7.24 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=2.0 Hz).

(111c)2,6-Difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the t-butyl[(2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate(0.74 g, 1.22 mmol) prepared in Example 111b, triethylsilane (0.97 mL),trifluoroacetic acid (1.2 mL) and dichloromethane (12 mL), to yield thetitle compound (232.9 mg, 54%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.72-1.95 (4H, m), 2.19-2.33 (2H, m),3.35-3.39 (1H, m), 3.82 (3H, s), 4.63-4.66 (1H, m), 5.76 (2H, brs), 6.06(1H, d, J=2.0 Hz), 6.41 (2H, d, J=10.7 Hz), 7.39 (1H, d, J=1.5 Hz).

(111d)2,6-Difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

A solution of the2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(0.23 g, 0.65 mmol) prepared in Example 111c, 2,4-difluoropyrimidine(0.23 g, 1.96 mmol) and potassium carbonate (0.36 g, 2.61 mmol) in DMF(6.5 mL) was stirred at 120° C. for 3 hours. After allowing to cool,water (50 mL) was added to the reaction solution, followed by extractionwith ethyl acetate (50 mL). The thus obtained organic layer was washedtwice with water (50 mL) and dried over anhydrous sodium sulfate. Aftervacuum concentration, the residue was purified with silica gelchromatography (ethyl acetate/methanol=6:1) to yield the title compound(150 mg, 51%) as a colorless amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.72-1.96 (4H, m), 2.20-2.36 (2H, m),3.35-3.40 (1H, m), 3.85 (3H, s), 4.63-4.66 (1H, m), 6.05 (1H, d, J=1.6Hz), 6.44 (2H, d, J=13.3 Hz), 7.19 (1H, dd, J=3.5, 5.9 Hz), 7.46 (1H, d,J=1.6 Hz), 8.40 (1H, dd, J=2.0, 5.5 Hz).

MS (ESI) m/z: 454 [M+H]+.

Example 1124-{[(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(112a)(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (650 mg, 7.92 mmol), n-butyllithium (2.69 M solution in hexane; 3.08 mL, 8.28 mmol),(1R*,3R*,6S*)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (Bioorg. Med.Chem. 2004, 12, 1459; 1.54 g, 7.54 mmol) and THF (45 mL), to yield thetitle compound (790 mg, 37%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.50-1.56 (2H, m), 1.84-1.91 (2H, m),2.09-2.15 (2H, m), 2.25 (1H, brs), 3.09-3.15 (1H, m), 3.61-3.67 (1H, m),3.73-3.74 (1H, m), 3.81 (3H, s), 4.50 (1H, d, J=11.7 Hz), 4.58 (1H, d,J=12.2 Hz), 6.05 (1H, d, J=2.0 Hz), 7.26-7.40 (6H, m).

Also, a by-product(1S*,2R*,5S*)-5-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(106 mg, 4.9%) was obtained as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.33-1.58 (3H, m), 1.91-1.95 (1H, m),2.15-2.19 (1H, m), 2.48-2.52 (1H, m), 2.60-2.65 (1H, m), 3.49-3.54 (1H,m), 3.60-3.65 (1H, m), 3.86 (3H, s), 4.60 (2H, s), 6.02 (1H, d, J=2.0Hz), 7.29-7.42 (6H, m).

(112b)4-{[(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(135 mg, 0.307 mmol) prepared in Example 14b, the(1S*,2R*,4R*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (80mg, 0.279 mmol) prepared in Example 112a, sodium hydride (63%; 16.0 mg,0.420 mmol) and DMF (2.0 mL), to yield the title compound (137 mg, 70%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.55-1.61 (1H, m), 1.73-1.79 (1H, m),1.87-2.04 (2H, m), 2.17-2.21 (1H, m), 2.27-2.30 (1H, m), 3.49-3.54 (1H,m), 3.76 (3H, s), 3.77 (3H, s), 3.82-3.83 (1H, m), 3.90 (3H, s),4.11-4.15 (1H, m), 4.53 (1H, d, J=12.2 Hz), 4.59 (1H, d, J=12.2 Hz),5.19 (1H, d, J=16.6 Hz), 5.23 (1H, d, J=17.1 Hz), 6.01 (1H, d, J=2.0Hz), 6.38-6.40 (2H, m), 6.47 (1H, dd, J=5.9, 10.7 Hz), 7.17-7.19 (2H,m), 7.30-7.37 (6H, m), 7.67 (1H, dd, J=6.4, 9.8 Hz), 8.45 (1H, d, J=5.9Hz), 8.78 (1H, s).

(112c)4-{[(1S*,2R*,4R*)-4-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R,4R*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(137 mg, 0.194 mmol) prepared in Example 112b, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (108 mg, 70%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.54-1.60 (1H, m), 1.73-1.79 (1H, m),2.00-2.05 (2H, m), 2.16-2.20 (1H, m), 2.27-2.29 (1H, m), 3.49-3.54 (1H,m), 3.82-3.83 (1H, m), 3.90 (3H, s), 4.10-4.15 (1H, m), 4.52 (1H, d,J=12.2 Hz), 4.59 (1H, d, J=12.2 Hz), 4.58-4.63 (1H, m), 6.03 (1H, brs),6.50 (1H, dd, J=6.4, 11.2 Hz), 7.22-7.39 (6H, m), 7.66 (1H, dd, J=6.8,9.8 Hz), 8.40 (1H, brs), 8.81 (1H, brs).

MS (ESI) m/z: 556 [M+H]+.

Example 1134-{[(1S*,2R*,5S*)-5-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(113a)4-{[(1S*,2R*,5S*)-5-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(81.5 mg, 0.185 mmol) prepared in Example 14b, the(1S*,2R*,5S*)-5-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(48.3 mg, 0.169 mmol) byproduct of Example 112a, sodium hydride (63%;9.6 mg, 0.252 mmol) and DMF (1.0 mL), to yield the title compound (94.3mg, 79%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.45-1.68 (3H, m), 2.04-2.08 (1H, m),2.27-2.30 (1H, m), 2.57-2.60 (1H, m), 2.98-3.03 (1H, m), 3.52-3.58 (1H,m), 3.76 (3H, s), 3.78 (3H, s), 3.90 (3H, s), 4.07-4.14 (1H, m), 4.57(1H, d, J=11.7 Hz), 4.62 (1H, d, J=11.7 Hz), 5.21 (2H, s), 5.98 (1H, d,J=2.0 Hz), 6.38-6.41 (3H, m), 7.17-7.20 (2H, m), 7.29-7.37 (6H, m), 7.69(1H, dd, J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, s).

(113b)4-{[(1S*,2R*,5S*)-5-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*,5S*)-5-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(94.3 mg, 0.134 mmol) prepared in Example 113a, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (56.0 mg, 75%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.45-1.68 (3H, m), 2.05-2.09 (1H, m),2.28-2.30 (1H, m), 2.57-2.59 (1H, m), 2.98-3.03 (1H, m), 3.54-3.59 (1H,m), 3.88 (3H, s), 4.09-4.14 (1H, m), 4.57 (1H, d, J=11.7 Hz), 4.62 (1H,d, J=11.7 Hz), 5.98 (1H, d, J=2.0 Hz), 6.46 (1H, dd, J=6.4, 10.7 Hz),7.14 (1H, d, J=6.9 Hz), 7.30-7.37 (6H, m), 7.68 (1H, dd, J=6.8, 10.3Hz), 8.34 (1H, brs), 8.62 (1H, brs).

MS (ESI) m/z: 556 [M+H]+.

Example 1142-Fluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

(114a) t-Butyl[(2,4-difluorophenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate

The reaction and aftertreatment were conducted in the same manner as inExample 111a by using 2,4-dimethoxybenzylamine (0.45 mL, 2.99 mmol),pyridine (1.21 mL, 15.0 mmol), dichloromethane (15 mL),2,4-difluorobenzenesulfonyl chloride (0.41 mL, 2.99 mmol), di-tert-butyldicarbonate (2.94 g, 13.5 mmol) and dimethylaminopyridine (0.15 g, 1.20mmol), to yield the title compound (0.40 g, 39%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.31 (9H, s), 3.82 (3H, s), 3.84 (3H, s),5.04 (2H, s), 6.47 (1H, d, J=2.4 Hz), 6.52 (1H, dd, J=2.4, 8.8 Hz),6.96-7.07 (2H, m), 7.27 (1H, d, J=8.3 Hz), 8.03-8.08 (1H, m).

(114b) t-Butyl(2,4-dimethoxybenzyl)[(2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl]carbamate

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the t-butyl[(2,4-difluorophenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate (0.40 g,0.90 mmol) prepared in Example 114a, the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (0.15 g, 0.90 mmol)prepared in Example 8a, sodium hydride (63%; 0.04 g, 1.08 mmol), DMF(4.5 mL) and water (0.02 mL), to yield the title compound (277.9 mg,52%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.28 (9H, s), 1.75-1.96 (4H, m),2.21-2.32 (2H, m), 3.37-3.41 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 3.84(3H, s), 4.69-4.72 (1H, m), 5.00 (2H, s), 6.06 (1H, d, J=2.0 Hz), 6.44(1H, d, J=2.4 Hz), 6.49 (1H, dd, J=2.4, 8.3 Hz), 6.59 (1H, dd, J=2.4,12.2 Hz), 6.67 (1H, dd, J=2.4, 8.8 Hz), 7.26 (1H, d, J=8.3 Hz), 7.42(1H, d, J=2.0 Hz), 7.88 (1H, d, J=8.3 Hz).

(114c)2-Fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the t-butyl (2,4-dimethoxybenzyl)[(2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl]carbamate(0.28 g, 0.47 mmol) prepared in Example 114b, triethylsilane (0.38 mL),trifluoroacetic acid (0.47 mL) and dichloromethane (4.7 mL), to yieldthe title compound (159.4 mg, 99%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.75-1.98 (4H, m), 2.21-2.35 (2H, m),3.38-3.42 (1H, m), 3.84 (3H, s), 4.69-4.72 (1H, m), 5.29 (2H, brs), 6.08(1H, d, J=2.0 Hz), 6.63-6.66 (2H, m), 7.41 (1H, d, J=2.0 Hz), 7.77 (1H,t, J=8.8 Hz).

(114d)2-Fluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 111d by using the2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide(0.16 g, 0.47 mmol) prepared in Example 114c, 2,4-difluoropyrimidine(0.16 g, 1.41 mmol), potassium carbonate (0.26 g, 1.88 mmol) and DMF(4.7 mL), to yield the title compound (143.6 mg, 70%) as a colorlessamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.75-1.97 (4H, m), 2.20-2.35 (2H, m),3.38-3.42 (1H, m), 3.88 (3H, s), 4.69-4.72 (1H, m), 6.08 (1H, d, J=2.0Hz), 6.61 (1H, d, J=12.2 Hz), 6.71 (1H, d, J=11.2 Hz), 7.10 (1H, dd,J=3.9, 5.9 Hz), 7.49 (1H, d, J=2.0 Hz), 7.94 (1H, t, J=8.3 Hz), 8.37(1H, dd, J=2.0, 5.9 Hz).

MS (ESI) m/z: 436 [M+H]+.

Example 1154-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(115a)N-(2,4-Dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.40 g, 0.95 mmol) prepared in Example 29a, the(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (0.17 g, 0.95 mmol)prepared in Example 37a, sodium hydride (63%; 4 mg, 1.14 mmol), DMF (4.8mL) and water (0.03 mL), to yield the title compound (453 mg, 82%) as acolorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.37 (3H, t, J=7.3 Hz), 1.71-1.93 (4H,m), 2.16-2.30 (2H, m), 3.37 (1H, dt, J=4.4, 7.8 Hz), 3.74 (3H, s), 3.79(3H, s), 4.10-4.15 (2H, m), 4.67-4.74 (1H, m), 5.27 (2H, s), 6.04 (1H,d, J=2.0 Hz), 6.40 (1H, dd, J=2.0, 10.7 Hz), 6.43 (1H, d, J=2.4 Hz),6.53 (1H, dd, J=2.4, 12.2 Hz), 6.66 (1H, dd, J=2.4, 11.2 Hz), 7.19-7.23(2H, m), 7.43 (1H, d, J=2.0 Hz), 7.93 (1H, t, J=8.8 Hz), 8.41 (1H, d,J=5.9 Hz), 8.74 (1H, s).

(115b)4-{[(1S*,2R*)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.45 g, 0.78 mmol) prepared in Example 115a, triethylsilane (0.62 mL),trifluoroacetic acid (0.78 mL) and dichloromethane (7.8 mL), to yieldthe title compound (173 mg, 52%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.3 Hz), 1.72-1.79 (1H,m), 1.86-1.95 (3H, m), 2.19-2.31 (2H, m), 3.37 (1H, dt, J=4.9, 8.3 Hz),4.09-4.19 (2H, m), 4.66-4.69 (1H, m), 6.03 (1H, d, J=2.0 Hz), 6.56 (1H,dd, J=2.4, 12.2 Hz), 6.66 (1H, dd, J=2.4, 9.3 Hz), 7.23 (1H, brs), 7.43(1H, d, J=2.0 Hz), 7.90 (1H, t, J=8.3 Hz), 8.39 (1H, d, J=5.9 Hz), 8.85(1H, s).

MS (ESI) m/z: 432 [M+H]+.

Example 1164-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2,6-difluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide

(116a) Tert-butyl1,3-thiazol-4-yl[(2,4,6-trifluorophenyl)sulfonyl]carbamate

The reaction and aftertreatment were conducted in the same manner as inExample 86a by using tert-butyl 1,3-thiazol-4-ylcarbamate (Synthesis,2010, 3152-3162; 1.00 g, 4.99 mmol), lithium bis(trimethylsilyl)amide(1.0 M solution in THF; 5.99 mL, 5.99 mmol),2,4,6-trifluorobenzenesulfonyl chloride (1.38 g, 5.99 mmol) and THF (15mL), to yield the title compound (1.53 g, 78%) as a pale yellow solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39 (9H, s), 6.84 (2H, t, J=8.3 Hz),7.52 (1H, d, J=2.4 Hz), 8.81 (1H, d, J=2.0 Hz).

(116b) Tert-butyl{[2,6-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)phenyl]sulfonyl}1,3-thiazol-4-ylcarbamate

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the tert-butyl1,3-thiazol-4-yl[(2,4,6-trifluorophenyl)sulfonyl]carbamate (491 mg, 1.24mmol) prepared in Example 116a, the(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(350 mg, 1.19 mmol) prepared in Example 34b, sodium hydride (63%; 67.7mg, 1.78 mmol) and DMF (3.0 mL), to yield the title compound (426 mg,54%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.37 (9H, s), 1.47-1.68 (6H, m),1.83-2.27 (8H, m), 3.53-3.58 (1H, m), 3.64-3.69 (1H, m), 3.96-4.01 (1H,m), 4.18-4.23 (1H, m), 5.33-5.37 (1H, m), 6.41 (2H, dd, J=6.4, 10.3 Hz),7.47 (1H, d, J=5.9 Hz), 7.49 (1H, d, J=2.4 Hz), 8.79 (1H, d, J=2.0 Hz).

(116c)2,6-Difluoro-4-{[(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using thetert-butyl{[2,6-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)phenyl]sulfonyl}1,3-thiazol-4-ylcarbamate(426 mg, 0.636 mmol) prepared in Example 116b, trifluoroacetic acid (1.0mL), dichloromethane (1.0 mL) and methanol (0.1 mL), to yield the titlecompound (167 mg, 54%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.60-1.68 (4H, m), 1.87-1.96 (2H, m),2.10-2.26 (2H, m), 3.57-3.62 (1H, m), 4.10-4.14 (1H, m), 6.25 (2H, d,J=10.7 Hz), 6.97 (1H, d, J=2.0 Hz), 7.70 (1H, s), 7.70 (1H, d, J=2.4Hz), 11.5 (1H, brs).

(116d)4-{[(1S*,2R*)-2-(3-Amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2,6-difluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide

To a solution of the2,6-difluoro-4-{[(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide(167 mg, 0.343 mmol) prepared in Example 116c in ethanol (4.0 mL) andwater (2.0 mL), ammonium chloride (92.0 mg, 1.72 mmol) and an ironpowder (57.6 mg, 1.03 mol) were added, and the reaction solution wasstirred for 2 hours under heated reflux. After allowing to cool, thereaction solution was filtered through celite, the filtrate was vacuumconcentrated, and the residue was purified with silica gelchromatography (dichloromethane/methanol=93:7) to yield the titlecompound (145 mg, 92%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.35-1.62 (4H, m), 1.81-2.18 (4H, m),2.60-2.64 (1H, m), 3.93-3.96 (1H, m), 6.34 (2H, d, J=11.2 Hz), 6.97 (1H,d, J=1.5 Hz), 7.10 (1H, s), 8.64 (1H, s).

MS (ESI) m/z: 456 [M+H]+.

Example 1174-{[(1S*,2R*)-3,3-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(117a)(1S*,2S*,3R*)-3-(Benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107a by using the(1S*,2R*,3R*)-3-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(1.56 g, 5.45 mmol) prepared in Example 100c, triethylamine (2.00 mL,14.4 mmol), benzoyl chloride (1.50 mL, 12.9 mmol) and dichloromethane(15 mL), to yield the title compound (1.81 g, 85%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.51 (3H, m), 1.93-1.95 (1H, m),2.24-2.29 (2H, m), 3.11 (1H, t, J=10.3 Hz), 3.49-3.45 (1H, m), 3.89 (3H,s), 4.13 (1H, d, J=11.2 Hz), 4.39 (1H, d, J=11.2 Hz), 5.16-5.22 (1H, m),6.09 (1H, d, J=2.0 Hz), 6.97 (2H, dd, J=1.5, 7.3 Hz), 7.23-7.27 (4H, m),7.34-7.37 (3H, m), 7.48-7.51 (1H, m), 7.79 (1H, dd, J=1.5, 8.3 Hz).

(117b) (1S*,2S*,3R*)-3-Hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 106b by using the(1S*,2S*,3R*)-3-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate (1.81 g, 4.64 mmol) prepared in Example 117a, palladium carbon(5%; 1.80 g) and ethanol (20 mL), to yield the title compound (600 mg,43%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.47-1.63 (2H, m), 1.94-1.98 (1H, m),2.05-2.06 (1H, m), 2.14-2.17 (1H, m), 2.25-2.27 (1H, m), 3.00 (1H, t,J=10.3 Hz), 3.78-3.82 (1H, m), 3.91 (3H, s), 5.11 (1H, dt, J=3.9, 10.3Hz), 6.16 (1H, d, J=2.0 Hz), 7.36-7.39 (3H, m), 7.50-7.53 (1H, m),7.80-7.82 (2H, m).

(117c) (1S*,2R*)-3,3-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

To a solution of the(1S*,2S*,3R*)-3-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate(550 mg, 1.83 mmol) prepared in Example 117b in dichloromethane (6.0mL), a Dess-Martin reagent (2.30 g, 5.42 mmol) was added, and thereaction solution was stirred for 2 hours. To the reaction solution,bis(2-methoxyethyl)amino sulfur trifluoride (3.50 mL, 17.9 mmol) wasadded, and the reaction solution was stirred for 3 hours. To thereaction solution, an aqueous sodium hydrogencarbonate solution (10 mL)was added, and an organic layer was extracted with dichloromethane (10mL). The thus obtained organic layer was dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withsilica gel chromatography (hexane/ethyl acetate=1:1) to yield the titlecompound (206 mg, 35%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.56-1.99 (4H, m), 2.29-2.40 (2H, m),3.45 (1H, ddd, J=2.9, 10.7, 24.4 Hz), 3.92 (3H, s), 5.39 (1H, dt, J=4.4,10.7 Hz), 6.30 (1H, t, J=2.0 Hz), 7.35-7.40 (3H, m), 7.50-7.53 (1H, m),7.78 (2H, dd, J=1.5, 8.3 Hz).

(117d) (1S*,2R*)-3,3-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 107e by using the(1S*,2R*)-3,3-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate(206 mg, 0.643 mmol) prepared in Example 117c, potassium carbonate (270mg, 1.95 mmol) and methanol (4.0 mL), to yield the title compound (600mg, 43%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.44-1.91 (4H, m), 2.16-2.26 (2H, m),2.71 (1H, d, J=3.4 Hz), 3.02 (1H, ddd, J=2.4, 10.3, 26.4 Hz), 3.82 (3H,s), 3.92-3.97 (1H, m), 6.29 (1H, t, J=2.4 Hz), 7.44 (1H, d, J=2.0 Hz).

(117e)4-{[(1S*,2R*)-3,3-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(219 mg, 0.498 mmol) prepared in Example 14b, the(1S*,2R*)-3,3-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (98.0mg, 0.453 mmol) prepared in Example 117d, sodium hydride (63%; 25.9 mg,0.680 mmol) and DMF (2.0 mL), to yield the title compound (260 mg, 90%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.60-2.00 (4H, m), 2.33-2.36 (2H, m),3.44 (1H, ddd, J=52.4, 10.7, 26.4 Hz), 3.76 (3H, s), 3.78 (3H, s), 3.91(3H, s), 4.46 (1H, dt, J=3.9, 10.3 Hz), 5.19 (1H, d, J=16.6 Hz), 5.23(1H, d, J=17.1 Hz), 6.24 (1H, t, J=2.4 Hz), 6.39-6.41 (2H, m), 6.53 (1H,dd, J=6.4, 10.7 Hz), 7.16 (1H, d, J=5.9 Hz), 7.19 (1H, d, J=8.8 Hz),7.36 (1H, d, J=2.0 Hz), 8.48 (1H, dd, J=6.4, 10.3 Hz), 8.46 (1H, d,J=5.9 Hz), 8.78 (1H, s).

(117f)4-{[(1S*,2R*)-3,3-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-3,3-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(260 mg, 0.398 mmol) prepared in Example 117e, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (221 mg, 90%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.60-2.01 (4H, m), 2.31-2.37 (2H, m),3.43 (1H, ddd, J=2.4, 10.7, 26.4 Hz), 3.91 (3H, s), 4.46 (1H, dt, J=3.9,10.7 Hz), 6.25 (1H, t, J=2.0 Hz), 6.57 (1H, dd, J=5.9, 10.7 Hz), 7.21(1H, d, J=6.4 Hz), 7.35 (1H, d, J=2.0 Hz), 7.67 (1H, dd, J=6.4, 9.8 Hz),8.39 (1H, d, J=6.4 Hz), 8.75 (1H, s).

MS (ESI) m/z: 486 [M+H]+.

Example 1184-{[(1R,2S)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(118a) (1R,2S)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentanol

The (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol prepared inExample 37a was optically resolved with CHIRALPAK AD-H (Daicel Corp.;hexane/ethanol=8:2) to yield the title compound as a colorless oil.

[α]_(D) ²⁵=−54.3 (c 1.03, MeOH).

(118b)N-(2,4-dimethoxybenzyl)-4-{[(1R,2S)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(73.0 g, 166 mmol) prepared in Example 30a, the(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (29.9 g, 166 mol)prepared in Example 118a, sodium hydride (63%; 7.64 g, 200 mmol) and DMF(600 mL), to yield the title compound (77.2 g, 78%) as a colorless oil.

(118c)4-{[(1R,2S)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of theN-(2,4-dimethoxybenzyl)-4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(77.2 g, 129 mmol) prepared in Example 118b and triethylsilane (23 mL)in dichloromethane (230 mL), trifluoroacetic acid (230 mL) was added atroom temperature, and the reaction solution was stirred for 1 hour. Thereaction solution was concentrated, and the residue was purified withsilica gel chromatography (ethyl acetate/methanol=9:1) to yield thetitle compound as a colorless solid. A suspension of this title compoundin ethyl acetate (200 mL) was further irradiated with ultrasonic wavefor 20 minutes. The suspension was filtered, and crystals collected byfiltration were washed with ethyl acetate and dried at 40° C. for 24hours to yield the title compound (44.4 g, 77%) as colorless crystals.

MS (ESI) m/z: 450 [M+H]+;

[α]_(D) ²⁵=−51.6 (c 1.00, DMSO).

The powder x-ray diffraction pattern of the crystals is shown in FIG. 1.Peaks having relative intensity of 11 or larger with the maximum peakintensity as 100 in FIG. 1 are shown in Table 2.

TABLE 2 Peak d Relative No. 2θ value intensity 1 7.30 12.10 48 2 14.646.05 21 3 15.30 5.79 18 4 16.60 5.34 11 5 19.40 4.57 13 6 21.40 4.15 257 22.06 4.03 35 8 23.40 3.80 100 9 23.82 3.73 21 10 29.54 3.02 49 1130.58 2.92 51

Example 1194-{[(1S,2R)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(119a) (1S,2R)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentanol

The (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol prepared inExample 37a was optically resolved with CHIRALPAK AD-H (Daicel Corp.;hexane/ethanol 8:2) to yield the title compound as a colorless oil.

[α]_(D) ²⁵=56.1 (c 1.00, MeOH).

(119b)N-(2,4-Dimethoxybenzyl)-4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(99.1 g, 226 mmol) prepared in Example 30a, the(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (40.7 g, 226 mol)prepared in Example 119a, sodium hydride (63%; 12.9 g, 339 mmol) and DMF(1.2 L), to yield the title compound (100.3 g, 74%) as a colorless oil.

(119c)4-{[(1S,2R)-2-(1-Ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

To theN-(2,4-dimethoxybenzyl)-4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(100.3 g, 167 mmol) prepared in Example 119b and triethylsilane (30 mL)in dichloromethane (300 mL), trifluoroacetic acid (300 mL) was addedwith cooling on ice, and the reaction solution was stirred at roomtemperature for 1 hour. The reaction solution was concentrated, and theresidue was purified with silica gel chromatography (ethylacetate/methanol=9:1) to yield the title compound as a colorless solid.A suspension of this title compound in ethyl acetate (200 mL) wasfurther irradiated with ultrasonic wave for 20 minutes. The suspensionwas filtered, and crystals collected by filtration were washed withethyl acetate and dried at 40° C. for 24 hours to yield the titlecompound (32.9 g, 44%) as colorless crystals.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.25 (3H, t, J=7.0 Hz), 1.64-1.91 (4H,m), 2.19-2.32 (2H, m), 3.47-3.50 (1H, m), 4.09 (2H, q, J=7.0 Hz),4.92-4.96 (1H, m), 6.17 (1H, d, J=1.5 Hz), 6.97 (1H, brs), 7.07 (1H, t,J=7.7 Hz), 7.34 (1H, d, J=1.5 Hz), 7.60-7.64 (1H, m), 8.23 (1H, brs),8.55 (1H, s), 13.2 (1H, brs).

MS (ESI) m/z: 450 [M+H]+;

[α]_(D) ²⁵=50.4 (c 1.05, DMSO).

The powder x-ray diffraction pattern of the crystals is shown in FIG. 2.Peaks having relative intensity of 11 or larger with the maximum peakintensity as 100 in FIG. 2 are shown in Table 3.

TABLE 3 Peak d Relative No. 2θ value intensity 1 7.30 12.10 66 2 14.646.05 36 3 15.30 5.79 22 4 16.56 5.35 11 5 19.40 4.57 12 6 21.40 4.15 247 22.04 4.03 58 8 23.38 3.80 100 9 23.82 3.73 18 10 29.54 3.02 73 1130.58 2.92 52

Example 1202,5-Difluoro-4-{[(1S*,2R*,4S*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(120a)(1S*,2R*,4S*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (2.13 g, 25.9 mmol), n-butyllithium (2.69 M solution in hexane; 10.3 mL, 27.7 mmol),tert-butyl(dimethyl)[(1R*,3S*,5S*)-6-oxabicyclo[3.1.0]hex-3-yloxy]silane (WO 2012/21591;5.56 g, 25.9 mmol) and THF (150 mL), to yield the title compound (1.42g, 18%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.12 (6H, s), 0.92 (9H, s), 1.85-2.02(3H, m), 2.29-2.34 (1H, m), 3.46-3.50 (1H, m), 3.92 (3H, s), 4.10-4.13(1H, m), 4.52-4.54 (1H, m), 5.90 (1H, d, J=2.0 Hz), 7.37 (1H, d, J=1.5Hz).

(120b)4-{[(1S*,2R*,4S*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(1.16 g, 2.64 mmol) prepared in Example 14b, the(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol(710 mg, 2.39 mmol) prepared in Example 120a, sodium hydride (63%; 137mg, 3.60 mmol) and DMF (5.0 mL), to yield the title compound (1.37 g,80%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.05 (3H, s), 0.07 (3H, s), 0.89 (9H, s),1.81-1.85 (1H, m), 1.90-1.98 (1H, m), 2.17-2.22 (1H, m), 2.52-2.58 (1H,m), 3.76 (3H, s), 3.79 (3H, s), 3.88-3.93 (1H, m), 3.90 (3H, s),4.45-4.47 (1H, m), 4.51-4.55 (1H, m), 5.22 (2H, s), 6.02 (1H, d, J=2.0Hz), 6.40-6.42 (2H, m), 6.46 (1H, dd, J=6.4, 11.2 Hz), 7.17-7.20 (2H,m), 7.39 (1H, d, J=1.0 Hz), 7.76 (1H, dd, J=6.8, 10.3 Hz), 8.45 (1H, d,J=6.4 Hz), 8.78 (1H, s).

(120c)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

A solution of the4-{[(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(1.25 g, 1.75 mmol) prepared in Example 120b and tetrabutyl ammoniumfluoride (1.0 M solution in THF; 5.24 mL, 5.25 mmol) in THF (8.0 mL) wasstirred at room temperature for 3 hours. To the reaction solution, 1 Mhydrochloric acid (10 mL) was added, followed by extraction with ethylacetate (100 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (methylene chloride/methanol) toyield the title compound (1.16 g, 99%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.92-2.03 (2H, m), 2.33-2.37 (1H, m),2.59-2.65 (1H, m), 3.77 (3H, s), 3.80 (3H, s), 3.90 (3H, s), 3.93-3.98(1H, m), 4.56-4.59 (2H, m), 5.22 (1H, d, J=17.1 Hz), 5.26 (1H, d, J=17.1Hz), 6.04 (1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.49 (1H, dd, J=6.4,10.7 Hz), 7.17-7.20 (2H, m), 7.40 (1H, d, J=2.0 Hz), 7.75 (1H, dd,J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=1.0 Hz).

(120d)N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(114 mg, 0.185 mmol) prepared in Example 120c, dimethyl sulfate (17.9μL, 0.189 mmol), sodium hydride (63%; 10.5 mg, 0.276 mmol) and THF (2.0mL), to yield the title compound (60.0 mg, 51%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90-1.98 (2H, m), 2.36-2.40 (1H, m),2.55-2.60 (1H, m), 3.33 (3H, s), 3.76 (3H, s), 3.79 (3H, s), 3.79-3.82(1H, m), 3.90 (3H, s), 3.97-3.98 (1H, m), 4.51-4.55 (1H, m), 5.21 (1H,d, J=17.8 Hz), 5.25 (1H, d, J=18.1 Hz), 6.05 (1H, s), 6.39-6.42 (2H, m),6.46 (1H, dd, J=6.4, 11.0 Hz), 7.17-7.20 (2H, m), 7.40 (1H, s), 7.75(1H, dd, J=6.4, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, s).

(120e)2,5-Difluoro-4-{[(1S*,2R*,4S*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(60.0 mg, 0.0975 mmol) prepared in Example 120d, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (40.0 mg, 88%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90-1.98 (2H, m), 2.37-2.41 (1H, m),2.59-2.63 (1H, m), 3.33 (3H, s), 3.77-3.81 (1H, m), 3.89 (3H, s),3.99-4.00 (1H, m), 4.53-4.58 (1H, m), 6.08 (1H, s), 6.56 (1H, dd, J=6.4,11.0 Hz), 7.13 (1H, brs), 7.39 (1H, s), 7.75 (1H, dd, J=6.4, 10.0 Hz),8.32 (1H, s), 8.61 (1H, s).

MS (FAB) m/z: 466 [M+H]+.

Example 1212,5-Difluoro-4-{[(1S*,2R*,4R*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(121a)(1S*,2R*,4R*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (1.13 g, 13.8 mmol), n-butyllithium (2.69 M solution in hexane, 5.47 mL, 14.7 mmol),tert-butyl(dimethyl)[(1R*,3S*,5S*)-6-oxabicyclo[3.1.0]hex-3-yloxy]silane (WO 2012/21591;2.95 g, 13.8 mmol) and THF (90 mL), to yield the title compound (710 mg,17%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.06 (3H, s), 0.07 (3H, s), 0.89 (9H, s),1.67-1.73 (1H, m), 1.89-1.93 (1H, m), 2.02-2.07 (1H, m), 2.46-2.52 (1H,m), 2.96-3.01 (2H, m), 3.78 (3H, s), 4.37-4.45 (2H, m), 6.11 (1H, d,J=1.5 Hz), 7.34 (1H, s).

(121b)4-{[(1S*,2R*,4R*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(1.16 g, 2.64 mmol) prepared in Example 14b, the(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol(710 mg, 2.39 mmol) prepared in Example 121a, sodium hydride (63%; 137mg, 3.60 mmol) and DMF (5.0 mL), to yield the title compound (1.52 g,89%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.09 (6H, s), 0.91 (9H, s), 1.84-1.90(1H, m), 2.04-2.10 (1H, m), 2.22-2.27 (1H, m), 2.53-2.58 (1H, m),3.44-3.49 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 3.85 (3H, s), 4.49-4.54(1H, m), 4.69-4.73 (1H, m), 5.21 (1H, d, J=17.1 Hz), 5.25 (1H, d, J=17.1Hz), 6.16 (1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.48 (1H, dd, J=5.9,10.7 Hz), 7.16 (1H, dd, J=1.5, 5.9 Hz), 7.20 (1H, d, J=8.3 Hz), 7.40(1H, d, J=2.0 Hz), 7.76 (1H, dd, J=6.8, 10.3 Hz), 8.45 (1H, d, J=5.9Hz), 8.78 (1H, d, J=1.0 Hz).

(121c)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the4-{[(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(1.39 g, 1.94 mmol) prepared in Example 121b, tetrabutyl ammoniumfluoride (1.0 M solution in THF; 5.82 mL, 5.82 mmol) and THF (8.0 mL),to yield the title compound (1.72 g, 99%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.96-2.07 (2H, m), 2.48-2.53 (1H, m),2.59-2.62 (1H, m), 3.43-3.46 (1H, m), 3.76 (3H, s), 3.80 (3H, s), 3.86(3H, s), 4.57-4.58 (1H, m), 4.85-4.88 (1H, m), 5.22 (2H, s), 6.22 (1H,d, J=2.0 Hz), 6.38-6.42 (2H, m), 6.77-6.81 (1H, m), 7.13-7.18 (2H, m),7.35-7.36 (1H, m), 7.69-7.72 (1H, m), 8.43-8.45 (1H, m), 8.77 (1H, s).

(121d)N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(120 mg, 0.199 mmol) prepared in Example 121c, dimethyl sulfate (18.8μL, 0.199 mmol), sodium hydride (63%; 11.1 mg, 0.291 mmol) and THF (2.0mL), to yield the title compound (65.0 mg, 53%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.87-1.95 (1H, m), 2.05-2.12 (1H, m),2.31-2.38 (1H, m), 2.60-2.68 (1H, m), 3.35 (3H, s), 3.46-3.53 (1H, m),3.77 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 4.05-4.14 (1H, m), 4.66-4.71(1H, m), 5.21 (1H, d, J=16.8 Hz), 5.25 (1H, d, J=16.8 Hz), 6.15 (1H, d,J=2.0 Hz), 6.40-6.42 (2H, m), 6.51 (1H, dd, J=6.3, 11.0 Hz), 7.16 (1H,dd, J=1.2, 7.0 Hz), 7.20 (1H, d, J=8.6 Hz), 7.41 (1H, d, J=2.0 Hz), 7.76(1H, dd, J=6.3, 9.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=1.1 Hz).

(121e)2,5-Difluoro-4-{[(1S*,2R*,4R*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(65.0 mg, 0.106 mmol) prepared in Example 121d, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (40.0 mg, 81%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.87-1.93 (1H, m), 2.05-2.11 (1H, m),2.33-2.38 (1H, m), 2.61-2.67 (1H, m), 3.35 (3H, s), 3.42-3.48 (1H, m),3.84 (3H, s), 4.05-4.10 (1H, m), 4.68-4.72 (1H, m), 6.15 (1H, s), 6.58(1H, dd, J=6.4, 11.2 Hz), 7.17 (1H, brs), 7.39 (1H, d, J=2.0 Hz), 7.74(1H, dd, J=6.8, 10.3 Hz), 8.35 (1H, brs), 8.67 (1H, brs).

MS (FAB) m/z: 466 [M+H]+.

Example 1225-Chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(122a) (1S,2R)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol prepared inExample 4a was optically resolved with CHIRALPAK IB (Daicel Corp.;hexane/ethanol=9:1) to yield the title compound as a colorless oil.

[α]_(D) ²⁵=33.3 (c 0.916, MeOH).

(122b)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.60 g, 1.32 mmol) prepared in Example 20a, the(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.19 g, 1.05 mmol)prepared in Example 122a, sodium hydride (63%; 0.050 g, 1.32 mmol), DMF(6.6 mL) and water (0.020 mL), to yield the title compound (0.371 g,50%) as a colorless solid.

(122c)5-Chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.371 g, 0.602 mmol) prepared in Example 122b and triethylsilane (0.48mL, 3.01 mmol) in dichloromethane (6.0 mL), trifluoroacetic acid (0.60mL) was added at room temperature, and the reaction solution was stirredfor 1 hour. The reaction solution was concentrated, and the residue waspurified with silica gel chromatography (ethyl acetate/methanol=6:1) toyield the title compound (0.28 g, 99%) as a colorless solid.

[α]_(D) ²⁵=2.28 (c 1.05, DMSO).

A suspension of the title compound (300 mg, 0.644 mmol) in ethyl acetate(3.0 mL) was stirred for 2 hours under heated reflux. The reactionsolution was cooled, and hexane (5.0 mL) was then added to the reactionsolution. The suspension was filtered, and crystals collected byfiltration were washed with hexane to yield the title compound (290 mg,97%) as colorless crystals 1.

The powder x-ray diffraction pattern of the colorless crystals 1 isshown in FIG. 3. Peaks having relative intensity of 12 or larger withthe maximum peak intensity as 100 in FIG. 3 are shown in Table 4.

TABLE 4 Peak d Relative No. 2θ value intensity 1 9.98 8.86 19 2 14.246.21 100 3 17.98 4.93 17 4 19.60 4.53 12 5 20.06 4.42 52 6 20.76 4.28 137 21.16 4.20 19 8 21.46 4.14 39 9 24.34 3.65 21 10 25.64 3.47 16 1127.10 3.29 17

The title compound (300 mg, 0.644 mmol) was further dissolved in adichloromethane/methanol mixed solution (10:1, 4.0 mL), and thissolution was concentrated. To the residue, hexane (5.0 mL) was added,and this suspension was irradiated with ultrasonic wave for 30 minutes.The suspension was filtered, and crystals collected by filtration werewashed with hexane to yield the title compound (295 mg, 98%) ascolorless crystals 2.

The powder x-ray diffraction pattern of the colorless crystals 2 isshown in FIG. 4. Peaks having relative intensity of 30 or larger withthe maximum peak intensity as 100 in FIG. 4 are shown in Table 5.

TABLE 5 Peak d Relative No. 2θ value intensity 1 9.02 9.80 55 2 14.825.97 100 3 15.22 5.82 30 4 17.76 4.99 34 5 19.30 4.60 66 6 20.00 4.44 327 20.52 4.32 64 8 22.26 3.99 36 9 23.32 3.81 98

Example 123 (1S,2R)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

(123a) 1-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

To a solution of 1-methylpyrazole (6.0 g, 73.1 mmol) andN,N,N′,N′-tetramethylethylenediamine (10.96 mL, 73.1 mmol) in THF (125mL), butyl lithium (2.69 M solution in hexane; 31.8 mL, 85.5 mmol) wasadded at −78° C. The reaction solution was stirred at −78° C. for 30minutes. Then, cyclohexanone (9.06 mL, 87.7 mmol) was added thereto, andthe mixture was stirred at room temperature for 15 hours. To thereaction solution, water (500 mL) was added, followed by extraction withethyl acetate (250 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=3:2), toyield the title compound (11.32 g, 86%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.60-1.84 (8H, m), 1.99-2.01 (2H, m),4.05 (3H, s), 6.08 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=1.5 Hz).

(123b) 5-(Cyclohex-1-en-1-yl)-1-methyl-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 99b by using the 1-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (11.32g, 62.8 mmol) prepared in Example 123a, p-toluenesulfonic acidmonohydrate (17.9 g, 94.1 mmol) and toluene (100 mL), to yield the titlecompound (8.89 g, 87%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) 5 ppm: 1.66-1.78 (4H, m), 2.19-2.28 (4H, m),3.85 (3H, s), 5.86-5.88 (1H, m), 6.08 (1H, d, J=1.5 Hz), 7.40 (1H, d,J=2.0 Hz).

(123c) (1S,2S)-1-(1-Methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol

The reaction and aftertreatment were conducted in the same manner as inExample 102a by using the 5-(cyclohex-1-en-1-yl)-1-methyl-1H-pyrazole(2.66 g, 16.4 mmol) prepared in Example 123b, methanesulfonamide (1.56g, 16.4 mmol), t-butanol (20 mL), water (20 mL) and AD-mixα(Sigma-Aldrich Corp.; 23.0 g), to yield the title compound (3.22 g, 99%)as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.29-1.89 (6H, m), 2.09-2.09 (1H, m),2.16-2.22 (1H, m), 4.05-4.10 (1H, m), 4.07 (3H, s), 4.80 (1H, brs), 6.08(1H, d, J=2.0 Hz), 7.39 (1H, d, J=2.0 Hz).

(123d) 1-Methyl-5-[(1S,6S)-7-oxabicyclo[4.1.0]hept-1-yl]-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 102b by using the(1S,2S)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (423 mg, 2.15mmol) prepared in Example 123c, trimethyl orthoacetate (0.688 mL, 5.38mmol), p-toluenesulfonic acid (20.5 mg, 0.11 mmol), dichloromethane (6.0mL), acetonitrile (6.0 mL), lithium bromide (466 mg, 5.38 mmol), acetylbromide (0.398 mL, 5.38 mmol), methanol (6.0 mL) and potassium carbonate(743 mg, 5.38 mmol), to yield the title compound (180 mg, 47%).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.29-1.61 (4H, m), 1.96-2.24 (1H, m),3.27-3.29 (1H, m), 3.92 (3H, s), 4.80 (1H, brs), 6.13 (1H, d, J=1.6 Hz),7.36 (1H, d, J=1.6 Hz).

(123e) (1S,2R)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 102c by using the1-methyl-5-[(1S,6S)-7-oxabicyclo[4.1.0]hept-1-yl]-1H-pyrazole (0.21 g,1.17 mmol) prepared in Example 123d, Raney nickel (2.0 g) andisopropanol (5.9 mL), to yield the title compound (0.060 g, 28%).

Example 1242-Fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(124a) (1S,2R)-2-(1-Methyl-1H-pyrazol-5-yl)cyclopentanol

The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol prepared inExample 8a was optically resolved with CHIRALPAK IC (Daicel Corp.;hexane/ethanol=8:2) to yield the title compound as a colorless oil.

[α]_(D) ²⁵=59.0 (c 0.30, MeOH).

(124b)N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(191 mg, 0.45 mmol) prepared in Example 29a, the(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (68 mg, 0.38 mmol)prepared in Example 124a, sodium hydride (63%; 28.7 mg, 0.75 mmol) andDMF (2.0 mL), to yield the title compound (198 mg, 93%) as a colorlessoil.

(124c)2-Fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of theN-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(8.35 g, 14.7 mmol) prepared in Example 124b and triethylsilane (11.75mL, 73.6 mmol) in dichloromethane (147 mL), trifluoroacetic acid (14.7mL) was added at room temperature, and the reaction solution was stirredfor 1 hour. The reaction solution was concentrated, and the residue waspurified with silica gel chromatography (ethyl acetate) to yield thetitle compound as a colorless solid. A suspension of this title compoundin a hexane/dichloromethane mixed solvent was further irradiated withultrasonic wave for 1 hour. The suspension was filtered, and crystalscollected by filtration were washed with hexane and dried at 40° C. for24 hours to yield the title compound (5.95 g, 97%) as colorlesscrystals.

[α]_(D) ²⁵=59.7 (c 1.01, DMSO).

The powder x-ray diffraction pattern of the crystals is shown in FIG. 5.Peaks having relative intensity of 24 or larger with the maximum peakintensity as 100 in FIG. 5 are shown in Table 6.

TABLE 6 Peak d Relative No. 2θ value intensity 1 7.18 12.30 24 2 9.329.48 31 3 11.94 7.41 25 4 14.60 6.06 100 5 15.60 5.68 58 6 15.98 5.54 577 18.08 4.90 55 8 18.94 4.68 56 9 20.26 4.38 62 10 21.18 4.19 76 1124.78 3.59 41

Example 1254-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

(125a)N-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 86a by using N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine(WO 2010/079443; 1.00 g, 3.98 mmol), lithium bis(trimethylsilyl)amide(1.0 M solution in THF; 4.78 mL, 4.78 mmol),2,4-difluoro-5-methylbenzenesulfonyl chloride (WO 2010/079443; 0.989 g,4.36 mmol) and THF (20 mL), to yield the title compound (1.16 g, 66%) asa colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.23 (3H, s), 3.71 (3H, s), 3.75 (3H, s),5.30 (2H, s), 6.29 (1H, d, J=2.0 Hz), 6.36 (1H, dd, J=2.4, 8.3 Hz), 6.83(1H, t, J=9.3 Hz), 7.24 (1H, d, J=8.3 Hz), 7.62 (1H, t, J=7.8 Hz), 8.80(1H, s).

(125b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(205 mg, 0.464 mmol) prepared in Example 125a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (100 mg,0.462 mmol) prepared in Example 47b, sodium hydride (63%; 26.1 mg, 0.696mmol), DMF (2.0 mL) and water (0.013 mL), to yield the title compound(78.8 mg, 27%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.89-2.11 (4H, m), 1.97 (3H, s),2.29-2.36 (1H, m), 2.68-2.74 (1H, m), 3.07-3.12 (1H, m), 3.68 (3H, s),3.74 (3H, s), 3.89 (3H, s), 4.36 (1H, dt, J=4.4, 10.7 Hz), 5.24 (1H, d,J=15.6 Hz), 5.29 (1H, d, J=14.6 Hz), 6.05 (1H, d, J=2.0 Hz), 6.27 (1H,d, J=2.4 Hz), 6.33-6.38 (2H, m), 7.22 (1H, d, J=8.3 Hz), 7.39 (1H, d,J=1.5 Hz), 7.47 (1H, d, J=7.3 Hz), 8.77 (1H, s).

(125c)4-{[(1S*,2R*)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(78.8 mg, 0.124 mmol) prepared in Example 125b, triethylsilane (0.20mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), toyield the title compound (48.6 mg, 81%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.87-2.23 (5H, m), 2.02 (3H, s),2.65-2.70 (1H, m), 3.33-3.37 (1H, m), 3.85 (3H, s), 4.60 (1H, dt, J=4.4,10.7 Hz), 6.20 (1H, d, J=2.0 Hz), 6.64 (1H, d, J=11.7 Hz), 7.33 (1H, d,J=2.0 Hz), 7.56 (1H, d, J=7.8 Hz), 8.52 (1H, s).

MS (ESI) m/z: 488 [M+H]+.

Example 1264-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(126a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(193 mg, 0.44 mmol) prepared in Example 43a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (80.0mg, 0.37 mmol) prepared in Example 88g, sodium hydride (63%; 28.2 mg,0.74 mmol) and DMF (1.0 mL), to yield the title compound (80.0 mg, 34%)as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.87-2.48 (6H, m), 2.04 (3H, s),3.38-3.45 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.90 (3H, s), 4.23 (1H,dt, J=3.1, 10.6 Hz), 5.23 (2H, s), 6.03 (1H, d, J=2.0 Hz), 6.34 (1H, d,J=11.7 Hz), 6.38-6.41 (2H, m), 7.19 (1H, d, J=8.6 Hz), 7.24-7.26 (1H,m), 7.38 (1H, d, J=2.0 Hz), 7.69 (1H, d, J=8.2 Hz), 8.43 (1H, d, J=6.3Hz), 8.76 (1H, d, J=0.8 Hz).

(126b)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(80.0 mg, 0.13 mmol) prepared in Example 126a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (61.0 mg, 99%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.83-2.45 (6H, m), 2.06 (3H, s),3.38-3.45 (1H, m), 3.89 (3H, s), 4.24 (1H, dt, J=3.5, 9.4 Hz), 6.04 (1H,d, J=2.0 Hz), 6.39 (1H, d, J=12.1 Hz), 7.19-7.21 (1H, m), 7.38 (1H, d,J=2.0 Hz), 7.70 (1H, d, J=8.2 Hz), 8.41 (1H, d, J=5.9 Hz), 8.80 (1H, s).

MS (ESI) m/z: 482 [M+H]+.

Example 1274-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(127a)4-({(1S*,2R*)-5,5-Difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.22 g, 0.50 mmol) prepared in Example 43a, the(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol(0.12 g, 0.42 mmol) prepared in Example 103c, sodium hydride (63%; 25mg, 0.63 mmol), DMF (6.0 mL) and water (0.0075 mL), to yield the titlecompound (0.22 g, 76%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.58-1.67 (3H, m), 1.88-2.03 (6H, m),2.15 (3H, s), 2.15-2.17 (1H, m), 2.23-2.27 (1H, m), 2.63-2.68 (1H, m),2.93-2.98 (1H, m), 3.62-3.67 (1H, m), 3.76 (3H, s), 3.79 (3H, s),3.97-4.00 (1H, m), 4.21-4.26 (1H, m), 5.25 (2H, s), 5.25-5.29 (1H, m),6.38-6.41 (3H, m), 7.19 (1H, d, J=8.3 Hz), 7.26-7.27 (1H, m), 7.41-7.42(2H, m), 7.71 (1H, d, J=8.3 Hz), 8.43 (1H, d, J=5.9 Hz), 8.77 (1H, s).

(127b)4-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 22c by using the4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.28 mmol) prepared in Example 127a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL), dichloromethane (2.0 mL) and methanol(2.0 mL), to yield the title compound (0.11 g, 85%) as a colorlesssolid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.74-1.83 (1H, m), 1.99-2.18 (4H, m),2.07 (3H, s), 2.50-2.55 (1H, m), 2.98-3.03 (1H, m), 4.60 (1H, dt, J=4.4,9.8 Hz), 6.90 (1H, d, J=12.7 Hz), 7.00 (1H, brs), 7.51 (2H, s), 7.64(1H, d, J=8.8 Hz), 8.31 (1H, brs), 8.58 (1H, s).

MS (ESI) m/z: 468 [M+H]+.

Example 1282-Fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(128a) (1R,2S)-2-(1-Methyl-1H-pyrazol-5-yl)cyclopentanol

The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol prepared inExample 8a was optically resolved with CHIRALPAK IC (Daicel Corp.;hexane/ethanol=8:2) to yield the title compound as a colorless oil.

[α]_(D) ²⁵=−53.3 (c 0.35, MeOH).

(128b)N-(2,4-Dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(421 mg, 1.00 mmol) prepared in Example 29a, the(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (150 mg, 0.83 mmol)prepared in Example 128a, sodium hydride (63%; 63.4 mg, 1.66 mmol) andDMF (2.0 mL), to yield the title compound (150 mg, 32%) as a colorlessoil.

(128c)2-Fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(150 mg, 0.26 mmol) prepared in Example 128b, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (98.0 mg, 89%) as a colorless solid.

[α]_(D) ²⁵=−53.0 (c 1.02, DMSO).

Example 1294-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(129a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(150 mg, 0.34 mmol) prepared in Example 27a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (61.6mg, 0.28 mmol) prepared in Example 88 g, sodium hydride (63%; 21.7 mg,0.57 mmol) and DMF (2.0 mL), to yield the title compound (85.9 mg, 47%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.86-2.47 (6H, m), 3.33-3.38 (1H, m),3.77 (3H, s), 3.81 (3H, s), 3.87 (3H, s), 4.24 (1H, dt, J=3.9, 10.3 Hz),5.23 (2H, s), 6.04 (1H, d, J=2.0 Hz), 6.30 (2H, d, J=10.3 Hz), 6.40-6.44(2H, m), 7.12 (1H, dd, J=1.5, 6.4 Hz), 7.21 (1H, d, J=8.3 Hz), 7.38 (1H,d, J=2.0 Hz), 8.44 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=1.0 Hz).

(129b)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(85.9 mg, 0.14 mmol) prepared in Example 129a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (58.0 mg, 88%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.88-2.45 (6H, m), 3.33-3.38 (1H, m),3.88 (3H, s), 4.25 (1H, dt, J=3.9, 10.3 Hz), 6.06 (1H, d, J=2.0 Hz),6.33 (2H, d, J=10.7 Hz), 7.38-7.40 (2H, m), 8.41 (1H, d, J=6.4 Hz), 8.85(1H, s).

MS (ESI) m/z: 486 [M+H]+.

Example 1304-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(130a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(167 mg, 0.40 mmol) prepared in Example 29a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (71.5mg, 0.33 mmol) prepared in Example 88 g, sodium hydride (63%; 25.2 mg,0.66 mmol) and DMF (2.0 mL), to yield the title compound (79.7 mg, 39%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.85-2.46 (6H, m), 3.34-3.39 (1H, m),3.76 (3H, s), 3.79 (3H, s), 3.89 (3H, s), 4.28 (1H, dt, J=3.9, 10.3 Hz),5.23 (2H, s), 6.04 (1H, d, J=2.0 Hz), 6.39-6.45 (3H, m), 6.59 (1H, dd,J=2.4, 11.2 Hz), 7.17-7.20 (2H, m), 7.36 (1H, d, J=1.5 Hz), 7.89 (1H, t,J=8.8 Hz), 8.42 (1H, d, J=5.9 Hz), 8.75 (1H, s).

(130b)4-{[(1S*,2R)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(79.7 mg, 0.13 mmol) prepared in Example 130a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (60 mg, 99%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) 5 ppm: 1.85-2.47 (6H, m), 3.33-3.39 (1H, m),3.89 (3H, s), 4.29 (1H, dt, J=3.9, 10.7 Hz), 6.06 (1H, d, J=2.0 Hz),6.47 (1H, dd, J=2.4, 11.7 Hz), 6.60 (1H, dd, J=2.4, 6.8 Hz), 7.23 (1H,d, J=5.9 Hz), 7.37 (1H, d, J=2.0 Hz), 7.87 (1H, t, J=8.8 Hz), 8.39 (1H,brs), 8.83 (1H, brs).

MS (ESI) m/z: 468 [M+H]+.

Example 1315-Chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(131a)5-Chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(167 mg, 0.37 mmol) prepared in Example 20a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (65.9mg, 0.30 mmol) prepared in Example 88 g, sodium hydride (63%; 23.2 mg,0.61 mmol) and DMF (2.0 mL), to yield the title compound (104 mg, 52%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.94-2.47 (6H, m), 3.44-3.50 (1H, m),3.76 (6H, s), 3.94 (3H, s), 4.25 (1H, dt, J=4.4, 10.3 Hz), 5.19 (1H, d,J=17.6 Hz), 5.23 (1H, d, J=17.1 Hz), 6.07 (1H, d, J=2.0 Hz), 6.39-6.42(3H, m), 7.17-7.20 (2H, m), 7.38 (1H, d, J=1.5 Hz), 7.96 (1H, d, J=7.3Hz), 8.47 (1H, d, J=5.9 Hz), 8.79 (1H, s).

(131b)5-Chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(104 mg, 0.16 mmol) prepared in Example 131a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (72.2 mg, 90%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.94-2.49 (6H, m), 3.44-3.49 (1H, m),3.94 (3H, s), 4.26 (1H, dt, J=4.4, 10.3 Hz), 6.09 (1H, d, J=2.4 Hz),6.46 (1H, d, J=11.2 Hz), 7.26-7.27 (1H, m), 7.38 (1H, d, J=1.5 Hz), 7.97(1H, d, J=7.3 Hz), 8.39 (1H, d, J=6.4 Hz), 8.79 (1H, s).

MS (ESI) m/z: 502 [M+H]+.

Example 1324-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(132a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(233 mg, 0.530 mmol) prepared in Example 30a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (101mg, 0.500 mmol) prepared in Example 107e, sodium hydride (63%; 29 mg,0.750 mmol), DMF (2.0 mL) and water (0.780 mL), to yield the titlecompound (164 mg, 53%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.35-2.46 (2H, m), 2.75-2.96 (2H, m),3.75-3.85 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 3.89 (3H, s), 4.76 (1H,q, J=7.3 Hz), 5.21 (1H, d, J=16.6 Hz), 5.26 (1H, d, J=16.6 Hz), 6.15(1H, d, J=2.0 Hz), 6.40-6.42 (2H, m), 6.57 (1H, t, J=7.3 Hz), 7.15-7.21(2H, m), 7.44 (1H, d, J=2.0 Hz), 7.71-7.75 (1H, m), 8.46 (1H, d, J=5.9Hz), 8.77 (1H, d, J=1.0 Hz).

(132b)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(161 mg, 0.259 mmol) prepared in Example 132a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (118 mg, 97%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.35-2.47 (2H, m), 2.76-2.98 (2H, m),3.75-3.80 (1H, m), 3.90 (3H, s), 4.75 (1H, q, J=6.8 Hz), 6.16 (1H, d,J=2.0 Hz), 6.58-6.62 (1H, m), 7.22-7.23 (1H, m), 7.46 (1H, d, J=2.0 Hz),7.70-7.73 (1H, m), 8.38 (1H, d, J=6.4 Hz), 8.78 (1H, s).

MS (ESI) m/z: 472 [M+H]+.

Example 1334-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(133a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(231 mg, 0.530 mmol) prepared in Example 43a, the(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (101mg, 0.500 mmol) prepared in Example 107e, sodium hydride (63%; 29 mg,0.750 mmol), DMF (2.0 mL) and water (0.780 mL), to yield the titlecompound (175 mg, 57%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.21 (3H, s), 2.29-2.43 (2H, m),2.76-2.89 (2H, m), 3.69-3.81 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 3.87(3H, s), 4.70 (1H, q, J=6.8 Hz), 5.24 (2H, s), 6.14 (1H, d, J=2.0 Hz),6.30 (1H, d, J=11.2 Hz), 6.39-6.42 (2H, m), 7.16-7.26 (2H, m), 7.44 (1H,d, J=2.0 Hz), 7.79 (1H, d, J=8.8 Hz), 8.43 (1H, d, J=6.4 Hz), 8.76 (1H,s).

(133b)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(171 mg, 0.277 mmol) prepared in Example 133a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (106 mg, 82%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.22 (3H, s), 2.27-2.43 (2H, m),2.75-2.89 (2H, m), 3.70-3.75 (1H, m), 3.87 (3H, s), 4.70 (1H, q, J=6.4Hz), 6.13 (1H, d, J=2.0 Hz), 6.36 (1H, d, J=11.7 Hz), 7.22 (1H, brs),7.43 (1H, d, J=2.0 Hz), 7.78 (1H, d, J=8.3 Hz), 8.40 (1H, d, J=6.4 Hz),8.81 (1H, brs).

MS (ESI) m/z: 468 [M+H]+.

Example 1345-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

(134a)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(280 mg, 0.606 mmol) prepared in Example 86a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (120 mg,0.555 mmol) prepared in Example 47b, sodium hydride (63%; 22.1 mg, 0.589mmol), DMF (2.0 mL) and water (0.011 mL), to yield the title compound(291 mg, 80%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.91-2.14 (4H, m), 2.30-2.35 (1H, m),2.66-2.71 (1H, m), 3.12-3.17 (1H, m), 3.66 (3H, s), 3.74 (3H, s), 3.93(3H, s), 4.34 (1H, dt, J=4.9, 10.7 Hz), 5.26 (1H, d, J=15.1 Hz), 5.32(1H, d, J=15.1 Hz), 6.09 (1H, d, J=2.0 Hz), 6.22 (1H, d, J=2.4 Hz), 6.34(1H, dd, J=2.4, 8.3 Hz), 6.37 (1H, d, J=11.2 Hz), 7.24 (1H, d, J=8.3Hz), 7.39 (1H, d, J=2.0 Hz), 7.69 (1H, d, J=7.3 Hz), 8.80 (1H, s).

(134b)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(291 mg, 0.442 mmol) prepared in Example 134a, triethylsilane (0.20 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (183 mg, 81%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.92-2.12 (4H, m), 2.29-2.34 (1H, m),2.65-2.72 (1H, m), 3.12-3.17 (1H, m), 3.97 (3H, s), 4.35 (1H, dt, J=4.4,10.7 Hz), 6.11 (1H, d, J=2.4 Hz), 6.46 (1H, d, J=11.2 Hz), 7.45 (1H, d,J=2.0 Hz), 7.92 (1H, d, J=7.3 Hz), 8.23 (1H, s).

MS (ESI) m/z: 508 [M+H]+.

Example 1354-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(135a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(233 mg, 0.530 mmol) prepared in the Example 27a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (101mg, 0.500 mmol) prepared in Example 107e, sodium hydride (63%; 29 mg,0.750 mmol), DMF (2.0 mL) and water (0.780 mL), to yield the titlecompound (98 mg, 32%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.29-2.40 (2H, m), 2.71-2.91 (2H, m),3.65-3.70 (1H, m), 3.76 (3H, s), 3.81 (3H, s), 3.83 (3H, s), 4.71 (1H,q, J=6.8 Hz), 5.25 (2H, s), 6.14 (1H, d, J=2.0 Hz), 6.36-6.44 (4H, m),7.12 (1H, dd, J=1.0, 5.9 Hz), 7.21 (1H, d, J=8.3 Hz), 7.42 (1H, d, J=2.0Hz), 8.44 (1H, d, J=5.9 Hz), 8.78 (1H, d, J=1.0 Hz).

(135b)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(98 mg, 0.158 mmol) prepared in Example 135a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (54 mg, 73%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.29-2.41 (2H, m), 2.73-2.89 (2H, m),3.65-3.70 (1H, m), 3.84 (3H, s), 4.68 (1H, q, J=6.8 Hz), 6.13 (1H, d,J=2.0 Hz), 6.39 (2H, d, J=10.7 Hz), 7.30 (1H, brs), 7.43 (1H, d, J=2.0Hz), 8.43 (1H, d, J=5.9 Hz), 8.78 (1H, brs).

MS (ESI) m/z: 472 [M+H]+.

Example 1364-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(136a)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(223 mg, 0.530 mmol) prepared in Example 29a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (101mg, 0.500 mmol) prepared in Example 107e, sodium hydride (63%; 29 mg,0.750 mmol), DMF (2.0 mL) and water (0.780 mL), to yield the titlecompound (105 mg, 35%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.31-2.42 (2H, m), 2.74-2.91 (2H, m),3.66-3.71 (1H, m), 3.77 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 4.73 (1H,q, J=6.4 Hz), 5.24 (2H, s), 6.14 (1H, s), 6.40-6.42 (2H, m), 6.52 (1H,dd, J=2.0, 11.2 Hz), 6.64 (1H, dd, J=2.0, 9.3 Hz), 7.19-7.21 (2H, m),7.44 (1H, s), 7.97 (1H, t, J=8.8 Hz), 8.43 (1H, d, J=5.9 Hz), 8.76 (1H,s).

(136b)4-{[(1S*,2R*)-4,4-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(105 mg, 0.174 mmol) prepared in Example 136a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (76 mg, 96%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 2.21-2.41 (2H, m), 2.71-2.79 (1H, m),2.95-3.08 (1H, m), 3.71-3.75 (1H, m), 3.77 (3H, s), 5.04 (1H, q, J=5.9Hz), 6.29 (1H, d, J=2.0 Hz), 6.88-7.05 (3H, m), 7.33 (1H, d, J=1.5 Hz),7.82 (1H, brs), 8.36 (1H, brs), 8.56 (1H, brs).

MS (ESI) m/z: 454 [M+H]+.

Example 1374-{[(1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(137a)4-{[(1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(175 mg, 0.401 mmol) prepared in Example 43a, the(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (72.3 mg,0.334 mmol) prepared in Example 102c, sodium hydride (63%; 25.5 mg,0.668 mmol) and DMF (2.0 mL), to yield the title compound (198 mg, 94%)as a colorless oil.

(137b)4-{[(1S,2R)-5,5-Difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(198 mg, 0.313 mmol) prepared in Example 137a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (80 mg, 53%) as a colorless solid.

[α]_(D) ²⁵=−12.4 (c 1.01, DMSO).

Example 1382-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(138a)(1S*,2R*)-2-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol

To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (3.04 g, 20.0mmol) in THF (30 mL), n-butyl lithium (1.63 M solution in hexane; 12.7mL, 20.7 mmol) was added dropwise at −78° C. for 7 minutes. The reactionsolution was stirred for 30 minutes, and boron trifluoride-ethyl ether(3.14 mL, 25.0 mmol) was then added thereto. The reaction solution wasfurther stirred for 10 minutes. Then, cyclopentene oxide (2.08 mL, 24.0mmol) was added thereto, and the reaction solution was stirred at −78°C. for 3 hours. To the reaction solution, a saturated aqueous solutionof sodium hydrogencarbonate (15 mL) was added, followed by extractionfour times with ethyl acetate (20 mL). The thus obtained organic layerwas dried over anhydrous sodium sulfate. After vacuum concentration, theresidue was purified with silica gel chromatography (hexane/ethylacetate=1:4) to yield the title compound (1.54 g, 33%) in the form of adiastereomeric mixture as a colorless oil.

(138b)N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(218 mg, 0.50 mmol) prepared in Example 43a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol(154 mg, 0.65 mmol) prepared in Example 138a, sodium hydride (63%; 38mg, 1.0 mmol), DMF (3.0 mL) and water (1.1 mL), to yield the titlecompound (165 mg, 51%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(138c)2-Fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide(155 mg, 0.238 mmol) prepared in Example 138b, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (108 mg, 99%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.80-1.94 (4H, m), 2.20 (3H, s),2.22-2.28 (2H, m), 3.38-3.42 (1H, m), 4.84-4.92 (1H, m), 6.19 (1H, d,J=2.4 Hz), 6.71 (1H, d, J=12.7 Hz), 7.97 (1H, d, J=5.9 Hz), 7.52 (1H, d,J=2.0 Hz), 7.75 (1H, d, J=8.3 Hz), 8.32 (1H, d, J=6.4 Hz), 8.57 (1H, s).

MS (ESI) m/z: 418 [M+H]+.

Example 1392,6-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(139a)N-(2,4-Dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(220 mg, 0.50 mmol) prepared in Example 27a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol(154 mg, 0.65 mmol) prepared in Example 138a, sodium hydride (63%; 38mg, 1.0 mmol), DMF (3.0 mL) and water (1.1 mL), to yield the titlecompound (122 mg, 37%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(139b)2,6-Difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide(121 mg, 0.185 mmol) prepared in Example 139a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (67 mg, 86%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.83-1.94 (4H, m), 2.17-2.29 (2H, m),3.42-3.46 (1H, m), 4.82-4.85 (1H, m), 6.20 (1H, d, J=2.4 Hz), 6.47 (2H,d, J=13.2 Hz), 7.45 (1H, d, J=7.3 Hz), 7.57 (1H, d, J=2.0 Hz), 8.41 (1H,d, J=6.4 Hz), 8.87 (1H, d, J=1.0 Hz), 10.06 (2H, brs).

MS (ESI) m/z: 422 [M+H]+.

Example 1405-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(140a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(228 mg, 0.50 mmol) prepared in Example 20a, the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol(154 mg, 0.65 mmol) prepared in Example 138a, sodium hydride (63%; 38mg, 1.0 mmol), DMF (3.0 mL) and water (1.1 mL), to yield the titlecompound (128 mg, 38%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(140b)5-Chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide(126 mg, 0.187 mmol) prepared in Example 140a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (63 mg, 77%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.89-2.01 (4H, m), 2.18-2.34 (2H, m),3.49-3.52 (1H, m), 5.03-5.04 (1H, m), 6.23 (1H, d, J=2.4 Hz), 6.72 (1H,d, J=11.7 Hz), 7.32 (1H, d, J=5.4 Hz), 7.56 (1H, d, J=2.0 Hz), 7.99 (1H,d, J=7.3 Hz), 8.40 (1H, d, J=6.4 Hz), 8.81 (1H, d, J=1.0 Hz).

MS (ESI) m/z: 438 [M+H]+.

Example 1415-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(141a)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(202 mg, 0.444 mmol) prepared in Example 20a, the(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (80.0mg, 0.370 mmol) prepared in Example 47b, sodium hydride (63%; 21.1 mg,0.555 mmol) and DMF (2.0 mL), to yield the title compound (212 mg, 88%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.84-2.14 (4H, m), 2.29-2.33 (1H, m),2.66-2.71 (1H, m), 3.12-3.17 (1H, m), 3.78 (3H, s), 3.78 (3H, s), 3.93(3H, s), 4.35 (1H, dt, J=5.9, 10.7 Hz), 5.20 (2H, s), 6.08 (1H, d, J=2.4Hz), 6.39-6.43 (3H, m), 7.17-7.19 (2H, m), 7.37 (1H, d, J=2.0 Hz), 7.96(1H, d, J=7.3 Hz), 8.47 (1H, d, J=5.9 Hz), 8.79 (1H, s).

(141b)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(212 mg, 0.325 mmol) prepared in Example 141a, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (135 mg, 83%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.91-2.14 (4H, m), 2.29-2.34 (1H, m),2.66-2.71 (1H, m), 3.12-3.17 (1H, m), 3.92 (3H, s), 4.37 (1H, dt, J=4.4,10.7 Hz), 6.09 (1H, d, J=2.0 Hz), 6.48 (1H, d, J=11.2 Hz), 7.19 (1H, d,J=6.4 Hz), 7.36 (1H, d, J=2.0 Hz), 7.97 (1H, d, J=7.3 Hz), 8.37 (1H, d,J=6.4 Hz), 8.70 (1H, s).

MS (ESI) m/z: 502 [M+H]+.

Example 1425-Chloro-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(142a) (1R,2S)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol prepared inExample 4a was optically resolved with CHIRALPAK IB (Daicel Corp.;hexane/ethanol=9:1) to yield the title compound as a colorless oil.

[α]_(D) ²⁵=−33.1 (c 1.09, MeOH).

(142b)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(23.1 g, 50.7 mmol) prepared in Example 20a, the(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (9.13 g, 50.7 mmol)prepared in Example 142a, sodium hydride (63%; 2.21 g, 50.6 mmol), DMF(500 mL) and water (0.91 mL), to yield the title compound (23.3 g, 75%)as a colorless solid.

(142c)5-Chloro-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 122c by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(23.3 g, 37.8 mmol) prepared in Example 142b, triethylsilane (28.3 mL,177 mmol), trifluoroacetic acid (50 mL) and dichloromethane (500 mL), toyield the title compound (15.4 g, 88%) as a colorless solid.

[α]_(D) ²⁵=−3.21 (c 1.02, DMSO).

Example 1434-{[(1S,2R)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(143a) 4,4-Difluoro-1-(1H-pyrazol-4-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 8a by using 4-iodo-1H-pyrazole (5.82 g, 30.0 mmol), butyllithium (2.69 M solution in hexane; 22.3 mL, 60.0 mmol),4,4-difluorocyclohexanone (4.43 g, 33.0 mmol) and THF (120 mL), to yieldthe title compound (2.32 g, 55%) as a pale yellow solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.95-2.05 (6H, m), 2.18-2.35 (2H, m),2.55 (1H, t, J=7.3 Hz), 7.55 (2H, s).

(143b) 4-(4,4-Difluorocyclohex-1-en-1-yl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 99b by using the 4,4-difluoro-1-(1H-pyrazol-4-yl)cyclohexanol(0.25 g, 1.24 mmol) prepared in Example 143a, p-toluenesulfonic acidmonohydrate (120 mg, 0.62 mmol) and toluene (3.0 mL), to yield the titlecompound (189 mg, 83%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.11-2.19 (2H, m), 2.57-2.69 (4H, m),5.82-5.84 (1H, m), 7.61 (2H, s).

(143c) (1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the 4-(4,4-difluorocyclohex-1-en-1-yl)-1H-pyrazole(0.30 g, 1.63 mmol) prepared in Example 143b, a borane-THF complex (0.95M solution in THF; 3.77 mL, 3.59 mmol), sodium perborate tetrahydrate(0.55 g, 3.59 mmol), THF (1.6 mL) and water (2.4 mL), to yield the titlecompound (0.31 g, 94%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.74-1.99 (4H, m), 2.15-2.22 (1H, m),2.52-2.59 (2H, m), 3.69 (1H, dt, J=4.4, 10.7 Hz), 7.52 (2H, s).

(143d)(1S*,2R*)-5,5-Difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol

A solution of the (1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexanol(0.24 g, 1.17 mmol) prepared in Example 143c, potassium carbonate (0.32g, 2.34 mmol) and 4-methoxybenzyl chloride (0.16 mL, 1.17 mmol) inacetonitrile (5.9 mL) was stirred at 80° C. for 12 hours. After allowingto cool, water (20 mL) was added to the reaction solution, and anorganic layer was extracted with ethyl acetate (20 mL). The thusobtained organic layer was dried over anhydrous sodium sulfate. Aftervacuum concentration, the residue was purified with silica gelchromatography to yield the title compound (92.9 mg, 25%) as a colorlesssolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.63-1.98 (4H, m), 2.11-2.18 (1H, m),2.41-2.54 (2H, m), 3.61 (1H, dt, J=4.4, 10.7 Hz), 3.80 (3H, s), 5.15(2H, s), 6.88 (2H, d, J=8.8 Hz), 7.19 (2H, d, J=8.3 Hz), 7.24 (1H, s),7.39 (1H, s).

(143e)(1S,2R)-5,5-Difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol

The(1S*,2R*)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanolprepared in Example 143d was optically resolved with CHIRALPAK IA(Daicel Corp.; hexane/isopropanol=8:2) to yield the title compound as acolorless solid.

(143f)4-({(1S,2R)-5,5-Difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.16 g, 0.37 mmol) prepared in Example 43a, the(1S,2R)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol(0.09 g, 0.29 mmol) prepared in Example 143e, sodium hydride (63%; 10mg, 0.37 mmol), DMF (1.8 mL) and water (0.010 mL), to yield the titlecompound (177.7 mg, 66%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.86-2.00 (3H, m), 2.07 (3H, s),2.12-2.25 (2H, m), 2.64-2.66 (1H, m), 2.90-2.94 (1H, m), 3.78 (3H, s),3.80 (3H, s), 3.81 (3H, s), 4.22 (1H, dt, J=4.4, 10.3 Hz), 5.13 (2H, s),5.26 (1H, d, J=16.6 Hz), 5.30 (1H, d, J=17.1 Hz), 6.38-6.43 (3H, m),6.85 (2H, d, J=6.4 Hz), 7.07 (2H, d, J=8.8 Hz), 7.12 (1H, s), 7.19-7.22(2H, m), 7.40 (1H, s), 7.72 (1H, d, J=7.8 Hz), 8.44 (1H, d, J=5.9 Hz),8.78 (1H, d, J=1.0 Hz).

(143g)4-{[(1S,2R)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

A solution of the4-({(1S,2R)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.15 g, 0.20 mmol) prepared in Example 143f, triethylsilane (0.16 mL)and trifluoroacetic acid (0.20 mL) in dichloromethane (2.0 mL) wasstirred at 140° C. for 1 hour under microwave irradiation. The reactionsolution was concentrated, and the residue was purified with silica gelchromatography (ethyl acetate) to yield the title compound (90 mg, 94%)as a colorless solid.

Example 1444-{[(1R,2S)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(144a)(1R,2S)-5,5-Difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol

The(1S*,2R*)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanolprepared in Example 143d was optically resolved with CHIRALPAK IA(Daicel Corp.; hexane/isopropanol=8:2) to yield the title compound as acolorless solid.

(144b)4-({(1R,2S)-5,5-Difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.15 g, 0.34 mmol) prepared in Example 43a, the(1R,2S)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol(0.09 g, 0.28 mmol) prepared in Example 144a, sodium hydride (63%; 10mg, 0.34 mmol), DMF (1.8 mL) and water (0.010 mL), to yield the titlecompound (158.3 mg, 62%) as a colorless amorphous solid.

(144c)4-{[(1R,2S)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 143g by using the4-({(1R,2S)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(0.15 g, 0.20 mmol) prepared in Example 144b, triethylsilane (0.16 mL),trifluoroacetic acid (0.20 mL) and dichloromethane (2.0 mL), to yieldthe title compound (60 mg, 63%) as a colorless solid.

[α]_(D) ²⁵=−23.1 (c 1.01, DMSO).

Example 1455-Chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamideNa salt

To a solution of the5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(0.12 g, 0.26 mmol) prepared in Example 122c in methanol (5.0 mL), a 2 Msodium hydroxide solution (0.13 mL, 0.262 mol) was added. The reactionsolution was concentrated and further freeze dried to yield the titlecompound (123 mg, 98%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.42-2.01 (7H, m), 2.22-2.24 (1H, m),3.09-3.14 (1H, m), 3.90 (3H, s), 4.40-4.41 (1H, m), 6.14 (1H, s), 6.69(1H, d, J=5.4 Hz), 6.81 (1H, d, J=11.2 Hz), 7.27 (1H, s), 7.82 (1H, d,J=6.8 Hz), 8.00 (1H, d, J=5.4 Hz), 8.30 (1H, s).

Example 1465-Chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(146a)5-Chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(274 mg, 0.600 mmol) prepared in Example 20a, the(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (101mg, 0.500 mmol) prepared in Example 107e, sodium hydride (63%; 29 mg,0.750 mmol), DMF (2.0 mL) and water (0.016 mL), to yield the titlecompound (316 mg, 99%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.29-2.46 (2H, m), 2.72-2.93 (2H, m),3.75 (3H, s), 3.78 (3H, s), 3.79-3.87 (1H, m), 3.93 (3H, s), 4.71 (1H,q, J=6.8 Hz), 5.20 (1H, d, J=16.6 Hz), 5.24 (1H, d, J=16.6 Hz), 6.15(1H, d, J=2.0 Hz), 6.37-6.40 (2H, m), 6.47 (1H, d, J=10.7 Hz), 7.17-7.18(2H, m), 7.42 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=7.3 Hz), 8.46 (1H, d,J=5.9 Hz), 8.78 (1H, d, J=1.0 Hz).

(146b)5-Chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(316 mg, 0.495 mmol) prepared in Example 146a, triethylsilane (0.30 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield thetitle compound (237 mg, 98%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.28-2.51 (2H, m), 2.72-2.79 (1H, m),2.95-3.06 (1H, m), 3.81-3.90 (1H, m), 3.87 (3H, s), 5.00 (1H, q, J=6.8Hz), 6.31 (1H, d, J=2.0 Hz), 6.93 (1H, d, J=11.2 Hz), 7.00 (1H, brs),7.39 (1H, d, J=2.0 Hz), 8.01 (1H, d, J=7.3 Hz), 8.24 (1H, brs), 8.52(1H, s).

MS (ESI) m/z: 488 [M+H]+.

Example 1474-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(147a) 4,4-Difluoro-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol

To a solution of 4-iodo-1-(methoxymethyl)-1H-pyrazole (Organic Letters,2007, 9, 4947-4950; 1.40 g, 5.88 mmol) in THF (15 mL), isopropylmagnesium chloride (2.0 M solution in THF; 3.8 mL, 7.64 mmol) was addedwith cooling on ice. The reaction solution was stirred for 30 minuteswith cooling on ice. Then, 4,4-difluorocyclohexanone (2.30 g, 17.6 mmol)was added thereto, and the mixture was stirred at room temperature for 1hour. To the reaction solution, an aqueous ammonium chloride solution(50 mL) was added, followed by extraction with ethyl acetate (50 mL).The thus obtained organic layer was dried over anhydrous sodium sulfate.After vacuum concentration, the residue was purified with silica gelchromatography (hexane/ethyl acetate=7:3) to yield the title compound(0.95 g, 66%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.97-2.07 (6H, m), 2.19-2.32 (2H, m),3.34 (3H, s), 5.36 (2H, s), 7.54 (1H, s), 7.56 (1H, s).

(147b) 4-(4,4-Difluorocyclohex-1-en-1-yl)-1-(methoxymethyl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 99b by using the4,4-difluoro-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol (0.20 g,0.81 mmol) prepared in Example 147a, p-toluenesulfonic acid (14 mg,0.081 mmol) and toluene (5.0 mL), to yield the title compound (0.18 g,97%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.11-2.20 (2H, m), 2.57-2.70 (4H, m),3.32 (3H, s), 5.36 (2H, s), 5.84-5.86 (1H, m), 7.52 (1H, s), 7.62 (1H,s).

(147c)(1S*,2R*)-5,5-Difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 33b by using the4-(4,4-difluorocyclohex-1-en-1-yl)-1-(methoxymethyl)-1H-pyrazole (0.25g, 1.09 mmol) prepared in Example 147b, a borane-THF complex (0.95 M;2.50 mL, 2.41 mmol), sodium perborate tetrahydrate (0.33 g, 2.18 mmol),THF (10 mL) and water (10 mL), to yield the title compound (0.13 g, 48%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.70-1.90 (4H, m), 2.15-2.22 (1H, m),2.48-2.59 (2H, m), 3.35 (3H, s), 3.66-3.71 (1H, m), 5.36 (2H, s), 7.49(1H, s), 7.50 (1H, s).

(147d)4-({(1S*,2R*)-5,5-Difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(205 mg, 0.48 mmol) prepared in Example 29a, the(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol(0.10 g, 0.40 mmol) prepared in Example 147c, sodium hydride (63%; 24mg, 0.60 mmol) and DMF (5.0 mL), to yield the title compound (0.18 g,69%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.88-2.01 (3H, m), 2.14-2.19 (1H, m),2.24-2.29 (1H, m), 2.65-2.71 (1H, m), 2.86-2.94 (1H, m), 3.21 (3H, s),3.77 (3H, s), 3.79 (3H, s), 4.25-4.31 (1H, m), 5.23 (2H, s), 5.28 (2H,s), 6.39-6.41 (2H, m), 6.52 (1H, dd, J=2.4, 11.7 Hz), 6.67 (1H, dd,J=2.4, 8.8 Hz), 7.20 (1H, d, J=8.3 Hz), 7.22 (1H, dd, J=1.5, 7.3 Hz),7.38 (1H, s), 7.44 (1H, s), 7.91 (1H, t, J=8.8 Hz), 8.43 (1H, d, J=5.9Hz), 8.76 (1H, d, J=1.0 Hz).

(147e)4-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of the4-({(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.12 g, 0.19 mmol) prepared in Example 147d and triethylsilane (0.15mL) in dichloromethane (4.0 mL), trifluoroacetic acid (3.0 mL) was addedat room temperature, and the reaction solution was stirred for 2 hours.The reaction solution was concentrated, then ethanol (1.0 mL) and 2 Mhydrochloric acid (4.0 mL) were added to the residue, and the mixturewas stirred at 100° C. for 3 hours. After allowing to cool, the reactionsolution was neutralized with sodium hydrogencarbonate, and theresulting solid was collected by filtration. The solid thus collected byfiltration was purified with silica gel chromatography(dichloromethane/methanol=95:5) to yield the title compound (40 mg, 48%)as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.73-1.81 (1H, m), 1.99-2.17 (4H, m),2.52-2.64 (1H, m), 2.94-2.99 (1H, m), 4.54 (1H, dt, J=4.4, 10.3 Hz),6.83 (1H, dd, J=2.4, 8.8 Hz), 6.90 (1H, dd, J=2.0, 12.2 Hz), 6.98 (1H,d, J=5.9 Hz), 7.50 (2H, s), 7.78 (1H, t, J=8.8 Hz), 8.29 (1H, brs), 8.56(1H, s), 12.70 (1H, brs).

MS (ESI) m/z: 454 [M+H]+.

Example 1482-Fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(148a)5-[(1R*,2S*)-2-(Benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a solution of the(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol(975 mg, 4.13 mmol) prepared in Example 138a in DMF (20 mL), sodiumhydride (63%; 236 mg, 6.19 mmol) and benzyl bromide (0.735 mL, 6.19mmol) were added, and the reaction solution was stirred at roomtemperature for 7 hours. To the reaction solution, water (50 mL) wasadded, followed by extraction with ethyl acetate (50 mL). The thusobtained organic layer was washed twice with water (50 mL) and driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography (hexane/ethyl acetate=7:3)to yield the title compound (1.15 g, 57%) in the form of adiastereomeric mixture as a colorless oil.

(148b) 5-[(1R*,2S*)-2-(Benzyloxy)cyclopentyl]-1H-pyrazole

To a solution of the5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.15 g, 3.52 mmol) prepared in Example 148a in dichloromethane (10 mL),trifluoroacetic acid (5.0 mL) was added at room temperature, and thereaction solution was stirred for 12 hours. The reaction solution wasconcentrated, and a saturated aqueous solution of sodiumhydrogencarbonate (50 mL) was added to the residue, followed byextraction with ethyl acetate (50 mL). The thus obtained organic layerwas washed with saturated saline (50 mL) and dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withsilica gel chromatography (hexane/ethyl acetate=1:1) to yield the titlecompound (840 mg, 98%) as a pale yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.73-1.92 (4H, m), 2.02-2.10 (1H, m),2.16-2.23 (1H, m), 3.16-3.21 (1H, m), 3.95 (1H, q, J=6.4 Hz), 4.47 (1H,d, J=11.2 Hz), 4.57 (1H, d, J=11.7 Hz), 6.08 (1H, d, J=2.9 Hz),7.26-7.34 (5H, m), 7.48 (1H, d, J=2.0 Hz).

(148c) 5-[(1R,2S)-2-(Benzyloxy)cyclopentyl]-1H-pyrazole

The 5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1H-pyrazole prepared inExample 148b was optically resolved with CHIRALPAK AD-H (Daicel Corp.;hexane/isopropanol=9:1) to yield the title compound as a pale yellowoil.

(148d)3-[(1R,2S)-2-(Benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A solution of the 5-[(1R,2S)-2-(benzyloxy)cyclopentyl]-1H-pyrazole (322mg, 1.33 mmol) prepared in Example 148c, 3,4-dihydro-2H-pyran (0.728 mL,7.98 mmol) and p-toluenesulfonic acid hydrate (50 mg, 0.266 mmol) indichloromethane (5.0 mL) was stirred for 3 hours under reflux. Afterallowing to cool, the reaction solution was vacuum concentrated, and theresidue was purified with silica gel chromatography (hexane/ethylacetate=7:3) to yield the title compound (402 mg, 93%) in the form of adiastereomeric mixture as a colorless oil.

(148e)(1S,2R)-2-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 106b by using the3-[(1R,2S)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(403 mg, 1.23 mmol) prepared in Example 148d, palladium carbon (5%; 400mg) and ethanol (20 mL) to yield the title compound (265 mg, 91%) in theform of a diastereomeric mixture as a colorless oil.

(148f)N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(239 mg, 0.55 mmol) prepared in Example 43a, the(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentanol(118 mg, 0.50 mmol) prepared in Example 148e, sodium hydride (63%; 29mg, 0.75 mmol), DMF (3.0 mL) and water (0.016 mL), to yield the titlecompound (267 mg, 82%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(148g)2-Fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide(265 mg, 0.407 mmol) prepared in Example 148f, triethylsilane (0.60 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield thetitle compound (168 mg, 99%) as a colorless solid.

[α]_(D) ²⁵=60.5 (c 1.02, DMSO).

Example 1492-Fluoro-5-methyl-4-{[(1R,2S)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(149a) 5-[(1S,2R)-2-(Benzyloxy)cyclopentyl]-1H-pyrazole

The 5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1H-pyrazole prepared inExample 148b was optically resolved with CHIRALPAK AD-H (Daicel Corp.;hexane/isopropanol=9:1) to yield the title compound as a pale yellowoil.

(149b)3-[(1S,2R)-2-(Benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The reaction and aftertreatment were conducted in the same manner as inExample 148d by using the5-[(1S,2R)-2-(benzyloxy)cyclopentyl]-1H-pyrazole (320 mg, 1.32 mmol)prepared in Example 149a, 3,4-dihydro-2H-pyran (0.723 mL, 7.92 mmol),p-toluenesulfonic acid hydrate (50 mg, 0.266 mmol) and dichloromethane(5.0 mL), to yield the title compound (421 mg, 98%) in the form of adiastereomeric mixture as a colorless oil.

(149c)(1R,2S)-2-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentanol

The reaction and aftertreatment were conducted in the same manner as inExample 106b by using the3-[(1S,2R)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol(419 mg, 1.28 mmol) prepared in Example 149b, palladium carbon (5%; 400mg) and ethanol (20 mL), to yield the title compound (269 mg, 89%) inthe form of a diastereomeric mixture as a colorless oil.

(149d)N-(2,4-Dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(239 mg, 0.55 mmol) prepared in Example 43a, the(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentanol(118 mg, 0.50 mmol) prepared in Example 149c, sodium hydride (63%; 29mg, 0.75 mmol), DMF (3.0 mL) and water (0.016 mL), to yield the titlecompound (227 mg, 70%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(149e)2-Fluoro-5-methyl-4-{[(1R,2S)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide(227 mg, 0.348 mmol) prepared in Example 149d, triethylsilane (0.60 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield thetitle compound (143 mg, 98%) as a colorless solid.

[α]_(D) ²⁵=−57.8 (c 1.02, DMSO).

Example 1505-Chloro-2-fluoro-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(150a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(251 mg, 0.55 mmol) prepared in Example 20, the(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentanol(118 mg, 0.50 mmol) prepared in Example 148e, sodium hydride (63%; 29mg, 0.75 mmol), DMF (3.0 mL) and water (0.016 mL), to yield the titlecompound (281 mg, 84%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(150b)5-Chloro-2-fluoro-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide(281 mg, 0.418 mmol) prepared in Example 150a, triethylsilane (0.60 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield thetitle compound (182 mg, 99%) as a colorless solid.

[α]_(D) ²⁵=65.0 (c 1.05, DMSO).

Example 1515-Chloro-2-fluoro-4-{[(1R,2S)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(151a)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(251 mg, 0.55 mmol) prepared in Example 20a, the(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentanol(118 mg, 0.50 mmol) prepared in Example 149c, sodium hydride (63%; 29mg, 0.75 mmol), DMF (3.0 mL) and water (0.016 mL), to yield the titlecompound (287 mg, 85%) in the form of a diastereomeric mixture as acolorless amorphous solid.

(151b)5-Chloro-2-fluoro-4-{[(1R,2S)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide(287 mg, 0.427 mmol) prepared in Example 151a, triethylsilane (0.60 mL),trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield thetitle compound (185 mg, 99%) as a colorless solid.

[α]_(D) ²⁵=−52.1 (c 1.04, DMSO).

Example 1525-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(152a)5-Chloro-4-({(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.22 g, 0.48 mmol) prepared in Example 20a, the(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol(0.10 g, 0.40 mmol) prepared in Example 147c, sodium hydride (63%; 24mg, 0.60 mmol) and DMF (5.0 mL), to yield the title compound (0.24 g,87%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.88-2.10 (3H, m), 2.17-2.31 (2H, m),2.65-2.69 (1H, m), 3.01-3.06 (1H, m), 3.22 (3H, s), 3.77 (3H, s), 3.78(3H, s), 4.21 (1H, dt, J=4.4, 10.3 Hz), 5.21 (2H, s), 5.27 (1H, d,J=10.7 Hz), 5.29 (1H, d, J=10.7 Hz), 6.39-6.41 (2H, m), 6.47 (1H, d,J=11.7 Hz), 7.18-7.20 (2H, m), 7.47 (1H, s), 7.50 (1H, s), 7.99 (1H, d,J=7.3 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, d, J=1.0 Hz).

(152b)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 147e by using the5-chloro-4-({(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(0.20 g, 0.29 mmol) prepared in Example 152a, triethylsilane (0.20 mL),dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL), ethanol (1.0mL) and 2 M hydrochloric acid (5.0 mL), to yield the title compound(0.060 g, 42%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.76-1.84 (1H, m), 2.00-2.19 (4H, m),2.55-2.59 (1H, m), 3.01-3.05 (1H, m), 4.67 (1H, dt, J=3.9, 9.3 Hz), 6.94(1H, brs), 7.15 (1H, d, J=12.2 Hz), 7.51 (2H, s), 7.81 (1H, d, J=7.8Hz), 8.23 (1H, brs), 8.56 (1H, s), 12.88 (1H, brs).

MS (ESI) m/z: 488 [M+H]+.

Example 1535-Chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2-oxo-2,3-dihydropyrimidin-4-yl)benzenesulfonamide

(153a) 2-(Benzyloxy)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine

To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine(2.50 g, 9.50 mmol) prepared in Example 95a and benzyl alcohol (1.97 mL,19.0 mmol) in DMF (48 mL), sodium hydride (0.90 g, 23.7 mmol) was added,and the reaction solution was stirred at room temperature for 6 hours.To the reaction solution, an aqueous ammonium chloride solution (200 mL)was added, followed by extraction with ethyl acetate (100 mL). The thusobtained organic layer was washed twice with water (200 mL) and driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography (hexane/ethyl acetate=1:2)to yield the title compound (3.29 g, 99%) as a colorless amorphoussolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.79 (3H, s), 3.82 (3H, s), 4.44 (2H,brs), 5.37 (2H, s), 6.01 (1H, brs), 6.42 (1H, dd, J=2.4, 8.3 Hz), 6.46(1H, d, J=2.4 Hz), 7.14 (1H, d, J=8.3 Hz), 7.26-7.35 (3H, m), 7.45-7.47(2H, m), 7.95 (1H, brs).

(153b)N-[2-(benzyloxy)pyrimidin-4-yl]-5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 86a by using the2-(benzyloxy)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 1.42mmol) prepared in Example 153a, 5-chloro-2,4-difluorobenzenesulfonylchloride (0.36 g, 1.57 mmol), lithium bis(trimethylsilyl)amide (1.0 Msolution in THF; 1.71 mL, 1.71 mmol) and THF (5.0 mL), to yield thetitle compound (487.8 mg, 61%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.81 (3H, s), 3.82 (3H, s), 5.24 (2H, s),5.29 (2H, s), 6.46-6.48 (2H, m), 6.81 (1H, d, J=5.4 Hz), 7.02 (1H, t,J=8.8 Hz), 7.27 (1H, d, J=9.3 Hz), 7.33-7.41 (5H, m), 8.21 (1H, t, J=7.3Hz), 8.31 (1H, d, J=5.9 Hz).

(153c)N-[2-(benzyloxy)pyrimidin-4-yl]-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-[2-(benzyloxy)pyrimidin-4-yl]-5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide(0.49 g, 0.87 mmol) prepared in Example 153b, the(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (0.13 g, 0.69 mmol)prepared in Example 122a, sodium hydride (63%; 0.030 g, 0.87 mmol), DMF(4.3 mL) and water (0.030 mL), to yield the title compound (479.7 mg,77%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.36-1.68 (4H, m), 1.85-1.94 (2H, m),2.04-2.07 (1H, m), 2.18-2.20 (1H, m), 3.02-3.07 (1H, m), 3.76 (3H, s),3.76 (3H, s), 3.91 (3H, s), 4.12-4.18 (1H, m), 5.16 (2H, s), 5.22 (2H,s), 6.03 (1H, d, J=2.0 Hz), 6.39-6.41 (2H, m), 6.45 (1H, d, J=11.7 Hz),6.83 (1H, d, J=5.4 Hz), 7.19 (1H, d, J=8.8 Hz), 7.26-7.36 (6H, m), 7.96(1H, d, J=7.3 Hz), 8.24 (1H, d, J=5.9 Hz).

(153d)5-Chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2-oxo-2,3-dihydropyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using theN-[2-(benzyloxy)pyrimidin-4-yl]-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}benzenesulfonamide(0.48 g, 0.66 mmol) prepared in Example 153c, triethylsilane (1.6 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (6.6 mL), to yield thetitle compound (285 mg, 89%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.68 (4H, m), 1.86-1.95 (2H, m),2.05-2.08 (1H, m), 2.19-2.23 (1H, m), 3.02-3.07 (1H, m), 3.92 (3H, s),4.18 (1H, dt, J=3.9, 10.3 Hz), 6.06 (1H, d, J=2.0 Hz), 6.42 (1H, brs),6.50 (1H, d, J=11.7 Hz), 7.35 (1H, d, J=2.0 Hz), 7.56-7.58 (1H, m), 7.85(1H, d, J=7.3 Hz), 11.82 (1H, brs).

MS (ESI) m/z: 482 [M+H]+;

[α]_(D) ²⁵=−13.9 (c 1.00, DMSO).

Example 1545-Chloro-2-fluoro-4-({(1S*,2R*)-2-[1-(¹³C,²H₃)methyl-1H-pyrazol-5-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

(154a) 1-(¹³C,²H₃)methyl-1H-pyrazole

To a solution of iodo (¹³C,²H₃)methane (5.00 g, 34.2 mmol) and1H-pyrazole (2.16 g, 31.7 mmol) in THF (20 mL), sodium hydride (63%;1.32 g, 34.5 mmol) was added with cooling on ice, and the mixture wasstirred at room temperature for 6 hours. To the reaction solution,methylene chloride (200 mL) was added, the resulting insoluble matterwas filtered off, and the filtrate was vacuum concentrated to yield thetitle compound (1.27 g, 47%) in a crude form as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 6.25 (1H, t, J=2.0 Hz), 7.35-7.36 (1H,m), 7.50 (1H, d, J=1.5 Hz).

(154b) (1S*,2R*)-2-[1-(¹³C,²H₃)methyl-1H-pyrazol-5-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using the 1-(¹³C,²H₃)methyl-1H-pyrazole (1.27 g, 14.8mmol) prepared in Example 154a, N,N,N′,N′-tetramethylethylenediamine(2.21 mL, 14.8 mmol), butyl lithium (2.69 M solution in hexane; 6.41 mL,17.2 mmol), cyclohexene oxide (1.79 mL, 17.7 mmol) and THF (30 mL), toyield the title compound (1.29 g, 48%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.30-1.46 (4H, m), 1.75-1.91 (4H, m),2.10-2.13 (1H, m), 2.57-2.62 (1H, m), 3.61-3.65 (1H, m), 6.08 (1H, d,J=2.0 Hz), 7.44 (1H, d, J=1.5 Hz).

(154c)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[1-(¹³C,²H₃)methyl-1H-pyrazol-5-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(3.19 g, 7.00 mmol) prepared in Example 20a, the(1S*,2R*)-2-[1-(¹³C,²H₃)methyl-1H-pyrazol-5-yl]cyclohexanol (1.29 g, 7.0mmol) prepared in Example 154b, sodium hydride (63%; 0.32 g, 8.40 mmol),DMF (20 mL) and water (0.13 mL), to yield the title compound (2.70 g,62%) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) 5 ppm: 1.39-1.67 (4H, m), 1.85-1.97 (2H, m),2.04-2.10 (1H, m), 2.18-2.23 (1H, m), 3.02-3.08 (1H, m), 3.76 (3H, s),3.77 (3H, s), 4.09-4.17 (1H, m), 5.21 (2H, s), 6.03 (1H, d, J=2.0 Hz),6.39-6.44 (3H, m), 7.17-7.22 (2H, m), 7.35 (1H, d, J=2.0 Hz), 7.93 (1H,d, J=7.4 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, d, J=0.78 Hz).

(154d)5-Chloro-2-fluoro-4-({(1S*,2R*)-2-[1-(¹³C,²H₃)methyl-1H-pyrazol-5-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[1-(¹³C,²H₃)methyl-1H-pyrazol-5-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(2.70 g, 4.35 mmol) prepared in Example 154c, triethylsilane (2.00 mL),trifluoroacetic acid (2.0 mL) and dichloromethane (20 mL), to yield thetitle compound (0.904 g, 44%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.39-1.69 (4H, m), 1.86-1.96 (2H, m),2.05-2.08 (1H, m), 2.17-2.22 (1H, m), 3.01-3.06 (1H, m), 4.11-4.16 (1H,m), 6.03 (1H, d, J=2.0 Hz), 6.47 (1H, d, J=11.7 Hz), 7.23 (1H, d, J=6.4Hz), 7.33 (1H, d, J=2.0 Hz), 7.94 (1H, d, J=7.8 Hz), 8.39 (1H, d, J=6.4Hz), 8.79 (1H, s).

MS (ESI) m/z: 468 [M−H]−.

Example 1554-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(155a) 1-[(2-Methoxyethoxy)methyl]-1H-pyrazole

To a solution of 1H-pyrazole (13.6 g, 200 mmol) andN,N-diisopropylethylamine (68 mL, 400 mmol) in dichloromethane (150 mL),2-methoxyethoxymethyl chloride (24.9 mL, 220 mmol) was added withcooling on ice. The reaction solution was stirred at room temperaturefor 2 hours, and an aqueous sodium hydrogencarbonate solution (500 mL)was then added to the reaction solution, followed by extraction threetimes with dichloromethane (500 mL). The organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=1:1) toyield the title compound (29.9 g, 96%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 3.36 (3H, s), 3.48-3.50 (2H, m),3.63-3.64 (2H, m), 5.52 (2H, s), 6.35 (1H, t, J=2.0 Hz), 7.56 (1H, d,J=1.0 Hz), 7.60 (1H, d, J=2.4 Hz).

(155b)(1S*,2R*,5R*)-5-(Benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol

To a solution of the 1-[(2-methoxyethoxy)methyl]-1H-pyrazole (3.13 g,20.1 mmol) prepared in Example 155a in THF (30 mL), butyl lithium (2.69M solution in hexane; 7.46 mL, 20.1 mmol) and a borontrifluoride-diethyl ether complex (6.30 mL, 50.1 mmol) were added inthat order at −78° C. The reaction solution was stirred at −78° C. for10 minutes. Then, (1S*,3R*,6R*)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane(J. Chem. Soc. Perkin Trans. 1 1997, 657; 3.41 g, 16.7 mmol) was addedthereto, and the mixture was stirred at −78° C. for 5 hours. To thereaction solution, an aqueous sodium hydrogencarbonate solution (100 mL)was added, followed by extraction three times with ethyl acetate (100mL). The thus obtained organic layer was dried over anhydrous sodiumsulfate. After vacuum concentration, the residue was purified withsilica gel chromatography (ethyl acetate) to yield the title compound(3.00 g, 55%) as a mixture (3.00 g, 55%) with(1S*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol.

(155c)(1S*,2R*,5R*)-5-(Benzyloxy)-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexylbenzoate

To a solution of the mixture (2.99 g, 8.30 mmol) of(1S*,2R*,5R*)-5-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanoland(1S*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanolprepared in Example 155b, triethylamine (4.62 mL, 33.2 mmol),4-(N,N-dimethylamino)pyridine (203 mg, 1.66 mmol) in dichloroethane (30mL), and benzoyl chloride (1.93 mL, 16.6 mmol) was added, and thereaction solution was stirred for 5 hours under heated reflux. To thereaction solution, water (100 mL) was added, and an organic layer wasextracted and then dried over anhydrous sodium sulfate. After vacuumconcentration, the residue was purified with column chromatography(hexane/ethyl acetate=1:9) to yield the title compound (2.72 g, 71%) asa mixture (2.72 g, 71%) with(1R*,2R*,4S*)-4-(benzyloxy)-2-[(1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexylbenzoate.

(155d)(1S*,2R*,5R*)-5-Hydroxy-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate

A solution of the mixture (2.72 g, 5.84 mmol) of(1S*,2R*,5R*)-5-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate and(1R*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate prepared in Example 155c and palladium carbon (5%; 3.00 g) inethanol (20 mL) was stirred at 50° C. for 11 hours under a hydrogenatmosphere. The reaction solution was filtered through celite, thefiltrate was concentrated, and the residue was purified with silica gelchromatography (ethyl acetate) to yield the title compound (1.06 g, 48%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.69-1.80 (2H, m), 1.90-1.97 (2H, m),2.06-2.13 (1H, m), 2.34-2.39 (1H, m), 3.26-3.31 (1H, m), 3.37 (3H, s),3.42-3.51 (2H, m), 3.55-3.65 (2H, m), 4.36 (1H, s), 5.45 (1H, d, J=11.7Hz), 5.59 (1H, dt, J=4.4, 10.7 Hz), 5.77 (1H, d, J=11.2 Hz), 6.24 (1H,d, J=2.0 Hz), 7.35-7.38 (3H, m), 7.51 (1H, t, J=7.3 Hz), 7.82-7.84 (2H,m).

Also, a by-product(1S*,2R*,4S*)-4-hydroxy-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate (825 mg, 38%) was obtained as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.56-1.68 (3H, m), 2.12-2.35 (3H, m),3.34-3.38 (1H, m), 3.38 (3H, s), 3.42-3.51 (2H, m), 3.53-3.64 (2H, m),3.86-3.92 (1H, m), 5.16 (1H, dt, J=4.4, 10.3 Hz), 5.42 (1H, d, J=11.2Hz), 5.76 (1H, d, J=11.2 Hz), 6.20 (1H, d, J=2.0 Hz), 7.35-7.38 (3H, m),7.51 (1H, t, J=7.3 Hz), 7.81-7.82 (2H, m).

(155e)(1S*,2R*)-2-[(1-[(2-Methoxyethoxy)methyl]-1H-pyrazol-5-yl]-5-oxocyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107c by using the(1S*,2R*,5R*)-5-hydroxy-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate (1.06 g, 2.83 mmol) prepared in Example 155d, a Dess-Martinreagent (1.80 g, 4.25 mmol) and dichloromethane (40 mL), to yield thetitle compound (945 mg, 90%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.89-1.98 (1H, m), 2.36-2.67 (4H, m),3.04 (1H, ddd, J=1.5, 4.9, 14.6 Hz), 3.36 (3H, s), 3.43-3.53 (2H, m),3.57-3.71 (3H, m), 5.48-5.53 (1H, m), 5.52 (1H, d, J=11.2 Hz), 5.82 (1H,d, J=11.2 Hz), 6.24 (1H, d, J=1.5 Hz), 7.38-7.43 (3H, m), 7.54 (1H, t,J=7.3 Hz), 7.85-7.87 (2H, m).

(155f)(1S*,2R*)-5,5-Difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 106c by using the(1S*,2R*)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}-5-oxocyclohexylbenzoate (940 mg, 2.52 mmol) prepared in Example 155e,bis(2-methoxyethyl)amino sulfur trifluoride (2.66 mL, 15.1 mmol) anddichloromethane (10 mL), to yield the title compound (465 mg, 43%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.80-2.29 (5H, m), 2.74-2.81 (1H, m),3.31-3.34 (1H, m), 3.36 (3H, s), 3.40-3.51 (2H, m), 3.53-3.65 (2H, m),5.41 (1H, dt, J=4.4, 10.7 Hz), 5.44 (1H, d, J=11.7 Hz), 5.76 (1H, d,J=11.2 Hz), 6.21 (1H, d, J=2.0 Hz), 7.36-7.39 (3H, m), 7.53 (1H, t,J=7.8 Hz), 7.81-7.83 (2H, m).

(155g)(1S*,2R*)-5,5-Difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 107e by using the(1S*,2R*)-5,5-difluoro-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexylbenzoate (463 mg, 1.17 mmol) prepared in Example 155f, potassiumcarbonate (16 mg, 0.117 mmol) and methanol (10 mL), to yield the titlecompound (307 mg, 90%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.71-1.99 (4H, m), 2.15-2.21 (1H, m),2.56-2.63 (1H, m), 2.73-2.79 (1H, m), 2.87-2.92 (1H, m), 3.30 (3H, s),3.44-3.46 (2H, m), 3.59-3.68 (2H, m), 3.85-3.91 (1H, m), 5.53 (1H, d,J=11.2 Hz), 5.65 (1H, d, J=11.2 Hz), 6.22 (1H, d, J=2.0 Hz), 7.50 (1H,d, J=1.5 Hz).

(155h)4-{[(1S*,2R*)-5,5-Difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(261 mg, 0.60 mmol) prepared in Example 43a, the(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol(145 mg, 0.50 mmol) prepared in Example 155g, sodium hydride (63%; 29.0mg, 0.75 mmol), DMF (8.0 mL) and water (0.016 mL), to yield the titlecompound (280 mg, 79%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.84-2.04 (3H, m), 1.98 (3H, s),2.12-2.18 (1H, m), 2.25-2.31 (1H, m), 2.68-2.74 (1H, m), 3.35 (3H, s),3.39-3.45 (2H, m), 3.47-3.55 (2H, m), 3.65-3.69 (1H, m), 3.76 (3H, s),3.78 (3H, s), 4.41 (1H, dt, J=3.9, 10.3 Hz), 5.23 (2H, s), 5.44 (1H, d,J=11.2 Hz), 5.83 (1H, d, J=11.7 Hz), 6.10 (1H, d, J=1.5 Hz), 6.38-6.44(3H, m), 7.19 (1H, d, J=8.8 Hz), 7.25 (1H, dd, J=1.5, 5.9 Hz), 7.41 (1H,d, J=2.0 Hz), 7.68 (1H, d, J=7.3 Hz), 8.43 (1H, d, J=5.9 Hz), 8.76 (1H,s).

(155i)4-{[(1S*,2R*)-5,5-Difluoro-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

To a solution of the4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(265 mg, 0.376 mmol) prepared in Example 155h and triethylsilane (0.50mL) in dichloroethane (5.0 mL), trifluoroacetic acid (5.0 mL) was addedat room temperature, and the reaction solution was stirred for 4 hours.The reaction solution was concentrated, then methanol (15 mL) and 6 Mhydrochloric acid (5.0 mL) were added to the residue, and the reactionsolution was stirred for 5 hours under heated reflux. To the reactionsolution, an aqueous sodium hydrogencarbonate solution (50 mL) wasadded, followed by extraction five times with a dichloromethane/methanol(10:1) mixed solvent (50 mL). The thus obtained organic layer was driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography(dichloromethane/methanol=10:1) to yield the title compound (125 mg,71%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.78-1.86 (1H, m), 2.00-2.23 (4H, m),2.00 (3H, s), 2.55-2.63 (1H, m), 3.15-3.20 (1H, m), 3.74-3.78 (1H, m),6.15 (1H, d, J=2.0 Hz), 6.88 (1H, d, J=12.2 Hz), 7.00 (1H, brs), 7.47(1H, brs), 7.62 (1H, d, J=8.3 Hz), 8.31 (1H, brs), 8.57 (1H, brs), 12.60(1H, brs).

MS (ESI) m/z: 468 [M+H]+.

Example 1565-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

(156a)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(129 mg, 0.283 mmol) prepared in Example 20a, the(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol(68 mg, 0.236 mmol) prepared in Example 155g, sodium hydride (63%; 13.0mg, 0.354 mmol), DMF (5.0 mL) and water (0.008 mL), to yield the titlecompound (105 mg, 61%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.87-2.16 (4H, m), 2.26-2.32 (1H, m),2.66-2.70 (1H, m), 3.35 (3H, s), 3.40-3.53 (4H, m), 3.65-3.69 (1H, m),3.76 (6H, s), 4.39 (1H, dt, J=4.4, 10.7 Hz), 5.20 (2H, s), 5.41 (1H, d,J=11.2 Hz), 6.02 (1H, d, J=11.2 Hz), 6.14 (1H, d, J=2.0 Hz), 6.38-6.40(2H, m), 6.49 (1H, d, J=11.2 Hz), 7.19 (2H, d, J=8.3 Hz), 7.40 (1H, d,J=2.0 Hz), 7.94 (1H, d, J=7.3 Hz), 8.47 (1H, d, J=5.4 Hz), 8.79 (1H, s).

(156b)5-Chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 155i by using the5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(105 mg, 0.145 mmol) prepared in Example 156a, triethylsilane (0.30 mL),trifluoroacetic acid (3.0 mL), dichloromethane (3.0 mL), 6 Mhydrochloric acid (5.0 mL) and methanol (15 mL), to yield the titlecompound (29 mg, 41%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.80-1.87 (1H, m), 1.99-2.28 (4H, m),2.55-2.64 (1H, m), 3.18-3.22 (1H, m), 4.86-4.91 (1H, m), 6.18 (1H, d,J=2.0 Hz), 6.95 (1H, brs), 7.13 (1H, d, J=11.7 Hz), 7.47 (1H, brs), 7.79(1H, d, J=7.3 Hz), 8.24 (1H, brs), 8.56 (1H, brs), 12.51 (1H, brs).

MS (ESI) m/z: 488 [M+H]+.

Example 1574-{[(1S*,2R*)-4,4-Difluoro-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

(157a)(1S*,2R*)-2-[1-[(2-Methoxyethoxy)methyl]-1H-pyrazol-5-yl]-4-oxocyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107c by using the by-product(1S*,2R*,4S*)-4-hydroxy-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexylbenzoate (825 mg, 2.20 mmol) of Example 155d, a Dess-Martin reagent(1.40 g, 3.31 mmol) and dichloromethane (10 mL), to yield the titlecompound (688 mg, 83%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.09-2.17 (1H, m), 2.25-2.32 (1H, m),2.54-2.66 (2H, m), 2.71-2.77 (1H, m), 2.94 (1H, dd, J=5.9, 15.1 Hz),3.33 (3H, s), 3.43-3.50 (2H, m), 3.58-3.69 (2H, m), 3.95 (1H, q, J=6.4Hz), 5.54 (1H, d, J=11.2 Hz), 5.55-5.58 (1H, m), 5.79 (1H, d, J=11.2Hz), 6.20 (1H, d, J=1.5 Hz), 7.44-7.47 (3H, m), 7.59 (1H, t, J=7.3 Hz),7.97-7.99 (2H, m).

(157b)(1S*,2R*)-4,4-Difluoro-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 106c by using the(1S*,2R*)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}-4-oxocyclohexylbenzoate (686 mg, 1.84 mmol) prepared in Example 157a,bis(2-methoxyethyl)amino sulfur trifluoride (1.94 mL, 11.1 mmol) anddichloromethane (10 mL), to yield the title compound (547 mg, 75%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.87-2.13 (3H, m), 2.25-2.32 (2H, m),2.51-2.57 (1H, m), 3.37 (3H, s), 3.47-3.56 (3H, m), 3.60-3.68 (2H, m),5.26 (1H, dt, J=3.4, 10.7 Hz), 5.44 (1H, d, J=11.2 Hz), 5.75 (1H, d,J=11.2 Hz), 6.21 (1H, d, J=2.0 Hz), 7.36-7.39 (3H, m), 7.53 (1H, t,J=7.3 Hz), 7.82-7.84 (2H, m).

(157c)(1S*,2R*)-4,4-Difluoro-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 107e by using the(1S*,2R*)-4,4-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexylbenzoate (547 mg, 1.39 mmol) prepared in Example 157b, potassiumcarbonate (19 mg, 0.139 mmol) and methanol (10 mL), to yield the titlecompound (404 mg, 99%) as a yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.75-1.81 (1H, m), 1.85-2.03 (2H, m),2.12-2.26 (2H, m), 2.31-2.38 (1H, m), 3.18-3.24 (1H, m), 3.31 (3H, s),3.43-3.51 (2H, m), 3.60-3.73 (3H, m), 5.53 (1H, d, J=10.7 Hz), 5.61 (1H,d, J=11.2 Hz), 6.22 (1H, s), 7.51 (1H, s).

(157d)4-{[(1S*,2R*)-4,4-Difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(785 mg, 1.81 mmol) prepared in Example 43a, the(1S*,2R*)-4,4-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol(404 mg, 1.39 mmol) prepared in Example 157c, sodium hydride (63%; 79.0mg, 2.08 mmol), DMF (6.0 mL) and water (0.045 mL), to yield the titlecompound (358 mg, 36%) as a colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.82-2.14 (3H, m), 2.00 (3H, s),2.22-2.31 (2H, m), 2.47-2.56 (1H, m), 3.36 (3H, s), 3.44-3.54 (2H, m),3.64-3.73 (3H, m), 3.75 (3H, s), 3.78 (3H, s), 4.32 (1H, dt, J=3.4, 10.3Hz), 5.24 (2H, s), 5.44 (1H, d, J=11.2 Hz), 5.81 (1H, d, J=11.2 Hz),6.13 (1H, d, J=2.0 Hz), 6.38-6.44 (3H, m), 7.18 (1H, d, J=7.8 Hz), 7.27(1H, d, J=6.4 Hz), 7.42 (1H, d, J=2.0 Hz), 7.68 (1H, d, J=7.8 Hz), 8.43(1H, d, J=5.9 Hz), 8.76 (1H, s).

(157e)4-{[(1S*,2R*)-4,4-Difluoro-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 155i by using the4-{[(1S*,2R*)-4,4-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(356 mg, 0.504 mmol) prepared in Example 157d, triethylsilane (0.50 mL),trifluoroacetic acid (5.0 mL), dichloromethane (5.0 mL), 6 Mhydrochloric acid (5.0 mL) and methanol (15 mL), to yield the titlecompound (155 mg, 66%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.60-1.67 (1H, m), 1.98 (3H, s),2.10-2.36 (5H, m), 3.20-3.26 (1H, m), 4.69-4.74 (1H, m), 6.11 (1H, d,J=2.0 Hz), 7.00-7.02 (2H, m), 7.45 (1H, brs), 7.59 (1H, d, J=7.8 Hz),8.35 (1H, brs), 8.58 (1H, brs), 12.59 (1H, brs).

MS (ESI) m/z: 468 [M+H]+.

Example 1585-Chloro-2-fluoro-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(158a)(1S*,2R*)-2-{1-[(2-Methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 155b by using the 1-[(2-methoxyethoxy)methyl]-1H-pyrazole (2.00g, 12.8 mmol) prepared in Example 155a, butyl lithium (2.69 M solutionin hexane; 4.76 mL, 12.8 mmol), a boron trifluoride-diethyl ethercomplex (2.68 mL, 21.3 mmol), cyclohexene oxide (1.05 g, 10.7 mmol) andTHF (100 mL), to yield the title compound (1.64 g, 60%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.30-1.48 (4H, m), 1.73-2.13 (3H, m),2.11-2.13 (1H, m), 2.77-2.82 (1H, m), 3.32 (3H, s), 3.45-3.47 (2H, m),3.57-3.68 (4H, m), 5.52 (1H, d, J=12.2 Hz), 5.64 (1H, d, J=11.2 Hz),6.18 (1H, d, J=2.0 Hz), 7.48 (1H, d, J=1.0 Hz).

(158b)(1S,2R)-2-{1-[(2-Methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol

The(1S*,2R*)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanolprepared in Example 158a was optically resolved with CHIRALFLASH IC(Daicel Corp.; hexane/isopropanol=1:1) to yield the title compound as acolorless oil.

(158c)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(280 mg, 0.614 mmol) prepared in Example 20a, the(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol (104mg, 0.409 mmol) prepared in Example 158b, sodium hydride (63%; 18.7 mg,0.491 mmol) and DMF (2.0 mL), to yield the title compound (242 mg, 86%)as a colorless amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.43-1.69 (4H, m), 1.84-1.95 (2H, m),2.08-2.21 (2H, m), 3.36 (3H, s), 3.43-3.55 (4H, m), 3.65-3.70 (1H, m),3.76 (6H, s), 4.17 (1H, dt, J=3.9, 10.2 Hz), 5.21 (2H, s), 5.40 (1H, d,J=11.3 Hz), 6.05 (1H, d, J=11.3 Hz), 6.10 (1H, d, J=2.0 Hz), 6.37-6.40(2H, m), 6.49 (1H, d, J=11.7 Hz), 7.16-7.19 (1H, m), 7.22 (1H, dd,J=1.6, 6.3 Hz), 7.38 (1H, d, J=1.6 Hz), 7.91 (1H, d, J=7.4 Hz), 8.46(1H, d, J=5.9 Hz), 8.79 (1H, d, J=0.8 Hz).

(158d)5-Chloro-2-fluoro-4-{[(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(154 mg, 0.223 mmol) prepared in Example 158c, triethylsilane (0.20 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (120 mg, 99%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.43-1.67 (4H, m), 1.85-1.94 (2H, m),2.08-2.21 (2H, m), 3.36 (3H, s), 3.42-3.45 (4H, m), 3.64-3.69 (1H, m),4.17 (1H, dt, J=3.9, 10.3 Hz), 5.38 (1H, d, J=11.2 Hz), 6.04 (1H, d,J=11.7 Hz), 6.11 (1H, s), 6.54 (1H, d, J=11.2 Hz), 7.25 (1H, d, J=6.4Hz), 7.37 (1H, s), 7.93 (1H, dd, J=2.0, 7.3 Hz), 8.37-8.39 (1H, m), 8.80(1H, s).

(158e)5-Chloro-2-fluoro-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

A solution of the5-chloro-2-fluoro-4-{[(1S,2R)-2-{¹⁻[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(120 mg, 0.222 mmol) prepared in Example 158d in 6 M HCl (5.0 mL) andmethanol (4.0 mL) was stirred for 5 hours under heated reflux. Thereaction solution was concentrated, and the residue was purified withsilica gel chromatography (dichloromethane/methanol=85:15) to yield thetitle compound (80.0 mg, 80%) as a pale yellow solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.43-1.65 (3H, m), 1.74-1.93 (3H, m),2.07-2.09 (1H, m), 2.27-2.29 (1H, m), 3.14-3.19 (1H, m), 4.61 (1H, dt,J=3.9, 10.3 Hz), 6.52 (1H, d, J=2.4 Hz), 7.06 (1H, d, J=12.2 Hz), 7.13(1H, d, J=6.4 Hz), 7.85 (1H, d, J=2.4 Hz), 7.94 (1H, d, J=7.3 Hz), 8.38(1H, d, J=6.8 Hz), 8.68 (1H, s).

MS (ESI) m/z: 452 [M+H]+;

[α]_(D) ²⁵=2.61 (c 0.998, DMSO).

Example 1595-Chloro-2-fluoro-4-{[(1R,2S)-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(159a)(1R,2S)-2-{1-[(2-Methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol

The(1S*,2R*)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanolprepared in Example 158a was optically resolved with CHIRALFLASH IC(Daicel Corp.; hexane/isopropanol=1:1) to yield the title compound as acolorless oil.

(159b)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(296 mg, 0.649 mmol) prepared in Example 20a, the(1R,2S)-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexanol (110mg, 0.432 mmol) prepared in Example 159a, sodium hydride (63%; 19.8 mg,0.520 mmol) and DMF (2.0 mL), to yield the title compound (188 mg, 63%)as a colorless amorphous solid.

(159c)5-Chloro-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(188 mg, 0.272 mmol) prepared in Example 159b, triethylsilane (0.20 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL), to yield thetitle compound (139 mg, 95%) as a colorless oil.

(159d)5-Chloro-2-fluoro-4-{[(1R,2S)-2-(1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 158e by using the5-chloro-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(139 mg, 0.257 mmol) prepared in Example 159c, 6 M HCl (5.0 mL) andmethanol (4.0 mL), to yield the title compound (101 mg, 73%) as a paleyellow solid.

[α]_(D) ²⁵=−2.52 (c 1.05, DMSO).

Example 1605-Chloro-2-fluoro-4-{[(1S*,2R*,5R*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(160a)(1S*,2R*,5R*)-5-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using the 1-methylpyrazole (500 mg, 6.09 mmol), n-butyllithium (2.69 M solution in hexane, 2.37 mL, 6.37 mmol),tert-butyl(dimethyl)[(1S*,3R*,6R*)-7-oxabicyclo[4.1.0]hept-3-yloxy]silane (J. Pharm.Pharmacol., 49, 835-842, 1997; 1.32 g, 5.78 mmol) and THF (30 mL), toyield the title compound (932 mg, 52%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.06 (3H, s), 0.08 (3H, s), 0.91 (9H, s),1.48-1.76 (3H, m), 1.87-2.14 (3H, m), 2.56-2.62 (1H, m), 3.87 (3H, s),4.03-4.08 (1H, m), 4.24-4.26 (1H, m), 6.11 (1H, d, J=2.0 Hz), 7.44 (1H,d, J=2.0 Hz).

(160b)4-{[(1S*,2R*,5R*)-5-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(91.6 mg, 0.201 mmol) prepared in Example 20a, the(1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(52.0 mg, 0.167 mmol) prepared in Example 160a, sodium hydride (63%; 9.6mg, 0.252 mmol) and DMF (1.0 mL), to yield the title compound (59.0 mg,47%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.10 (6H, s), 0.96 (9H, s), 1.61-1.66(2H, m), 1.82-1.88 (2H, m), 2.14-2.25 (2H, m), 3.04-3.08 (1H, m), 3.76(3H, s), 3.77 (3H, s), 3.96 (3H, s), 4.30-4.32 (1H, m), 4.62 (1H, dt,J=3.9, 10.7 Hz), 5.18 (1H, d, J=16.6 Hz), 5.25 (1H, d, J=16.6 Hz), 6.05(1H, d, J=2.0 Hz), 6.39-6.41 (2H, m), 6.50 (1H, d, J=11.7 Hz), 7.18-7.20(2H, m), 7.36 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=7.3 Hz), 8.46 (1H, d,J=5.9 Hz), 8.79 (1H, d, J=1.0 Hz).

(160c)5-Chloro-2-fluoro-4-{[(1S*,2R*,5R*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the4-{[(1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(59.0 mg, 0.0791 mmol) prepared in Example 160b, triethylsilane (0.050mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), toyield the title compound (9.5 mg, 25%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.70-1.92 (4H, m), 2.10-2.19 (1H, m),2.33-2.35 (1H, m), 3.17-3.22 (1H, m), 3.91 (3H, s), 4.28-4.30 (1H, m),4.75 (1H, dt, J=3.9, 10.3 Hz), 6.15 (1H, d, J=2.0 Hz), 6.93 (1H, d,J=11.7 Hz), 7.01 (1H, d, J=6.4 Hz), 7.28 (1H, d, J=2.0 Hz), 7.91 (1H, d,J=7.3 Hz), 8.25 (1H, brs), 8.53 (1H, s). MS (ESI) m/z: 482 [M+H]+.

Example 1615-Chloro-2-fluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(161a)(1S*,2R*,4R*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 4a by using 1-methylpyrazole (500 mg, 6.09 mmol), n-butyllithium (2.69 M solution in hexane, 2.37 mL, 6.37 mmol),tert-butyl(dimethyl)[(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]hept-3-yloxy]silane(J. Pharm. Pharmacol., 49, 835-842, 1997; 1.32 g, 5.78 mmol) and THF (30mL), to yield the title compound (1.23 g, 69%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.06 (3H, s), 0.07 (3H, s), 0.93 (9H, s),1.49-1.61 (3H, m), 1.78-1.97 (3H, m), 3.18-3.23 (1H, m), 3.64-3.68 (1H,m), 3.85 (3H, s), 4.05-4.07 (1H, m), 6.07 (1H, d, J=2.0 Hz), 7.44 (1H,d, J=1.5 Hz).

(161b)4-{[(1S*,2R*,4R*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(91.6 mg, 0.201 mmol) prepared in Example 20a, the(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(52.0 mg, 0.167 mmol) prepared in Example 161a, sodium hydride (63%; 9.6mg, 0.252 mmol) and DMF (1.0 mL), to yield the title compound (90.0 mg,72%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.08 (3H, s), 0.09 (3H, s), 0.94 (9H, s),1.60-2.09 (6H, m), 3.58-3.63 (1H, m), 3.76 (6H, s), 3.93 (3H, s),4.13-4.17 (2H, m), 5.21 (2H, s), 5.98 (1H, d, J=2.0 Hz), 6.38-6.41 (2H,m), 6.45 (1H, d, J=11.7 Hz), 7.21 (1H, d, J=9.3 Hz), 7.23 (1H, dd,J=1.0, 5.9 Hz), 7.34 (1H, d, J=1.5 Hz), 7.92 (1H, d, J=7.8 Hz), 8.46(1H, d, J=5.9 Hz), 8.79 (1H, d, J=1.0 Hz).

(161c)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the4-{[(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(90.0 mg, 0.120 mmol) prepared in Example 161b, tetrabutyl ammoniumfluoride (1.0 M solution in THF; 0.241 mL, 0.241 mmol) and THF (5.0 mL),to yield the title compound (65.3 mg, 86%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.83-2.17 (6H, m), 3.59-3.65 (1H, m),3.76 (6H, s), 3.95 (3H, s), 4.14-4.19 (1H, m), 4.23-4.26 (1H, m), 5.21(2H, s), 6.02 (1H, d, J=2.0 Hz), 6.38-6.40 (2H, m), 6.43 (1H, d, J=11.7Hz), 7.18 (1H, d, J=9.3 Hz), 7.22 (1H, dd, J=1.0, 5.9 Hz), 7.35 (1H, d,J=2.0 Hz), 7.93 (1H, d, J=7.8 Hz), 8.46 (1H, d, J=5.9 Hz), 8.79 (1H, s).

(161d)5-Chloro-2-fluoro-4-{[(1S*,2R,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(65.3 mg, 0.103 mmol) prepared in Example 161c, triethylsilane (0.050mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), toyield the title compound (32.6 mg, 71%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.77-2.04 (6H, m), 3.56-3.61 (1H, m),3.90 (3H, s), 4.10-4.13 (1H, m), 4.51-4.56 (1H, m), 6.15 (1H, d, J=2.0Hz), 6.97 (1H, d, J=12.2 Hz), 7.00 (1H, d, J=6.4 Hz), 7.26 (1H, d, J=2.0Hz), 7.90 (1H, d, J=7.3 Hz), 8.25 (1H, d, J=6.4 Hz), 8.53 (1H, s).

MS (ESI) m/z: 482 [M+H]+.

Example 1625-Chloro-2-fluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(162a)(1S*,2R*,4R*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107a by using the(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(1.07 g, 3.45 mmol) prepared in Example 161a, triethylamine (2.88 mL,20.7 mmol), benzoyl chloride (2.00 mL, 17.2 mmol) and dichloromethane(10 mL), to yield the title compound (1.30 g, 91%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.09 (3H, s), 0.10 (3H, s), 0.96 (9H, s),1.67-1.75 (2H, m), 1.83-1.87 (1H, m), 1.95-2.05 (3H, m), 3.52-3.58 (1H,m), 3.87 (3H, s), 4.12-4.14 (1H, m), 5.11-5.16 (1H, m), 6.05 (1H, d,J=2.0 Hz), 7.33 (1H, d, J=2.0 Hz), 7.38 (2H, t, J=7.3 Hz), 7.51 (1H, tt,J=1.5, 7.3 Hz), 7.85-7.87 (2H, m).

(162b) (1S*,2R*,4R*)-4-Hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate (1.30 g, 3.14 mmol) prepared in Example 162a, tetrabutylammonium fluoride (1.0 M solution in THF; 9.42 mL, 9.42 mmol) and THF(5.0 mL), to yield the title compound (867 mg, 92%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.78-2.12 (6H, m), 3.53-3.58 (1H, m),3.89 (3H, s), 4.22-4.25 (1H, m), 5.11-5.16 (1H, m), 6.08 (1H, d, J=1.5Hz), 7.34 (1H, d, J=2.0 Hz), 7.39 (2H, t, J=7.3 Hz), 7.52 (1H, tt,J=1.5, 7.3 Hz), 7.86-7.88 (2H, m).

(162c) (1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)-4-oxocyclohexyl benzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107c by using the(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate(439 mg, 1.46 mmol) prepared in Example 162b, a Dess-Martin reagent(1.24 g, 2.92 mmol) and dichloromethane (10 mL), to yield the titlecompound (430 mg, 99%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.10-2.16 (1H, m), 2.20-2.27 (1H, m),2.54-2.59 (1H, m), 2.63-2.67 (1H, m), 2.76-2.82 (1H, m), 2.90-2.94 (1H,m), 3.79 (1H, q, J=5.9 Hz), 4.00 (3H, s), 5.42-5.45 (1H, m), 6.10 (1H,d, J=2.0 Hz), 7.40 (1H, d, J=2.0 Hz), 7.48 (2H, t, J=7.3 Hz), 7.61 (1H,tt, J=1.0, 7.8 Hz), 8.02-8.04 (2H, m).

(162d) (1S*,2R*,4S*)-4-Hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

To a solution of the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)-4-oxocyclohexyl benzoate (430 mg,1.44 mmol) prepared in Example 162c in ethanol (7.0 mL), sodiumborohydride (164 mg, 4.34 mmol) was added, and the mixture was stirredat room temperature for 5 hours. To the reaction solution, water (10 mL)was added, followed by extraction with ethyl acetate (50 mL). The thusobtained organic layer was washed twice with water (50 mL) and driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with reverse phase chromatography (YMC HPLC COLUMN,YMC-Pack ODS-A; methanol/water=6:4) to yield the title compound (293 mg,69%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.59-1.70 (3H, m), 2.12-2.29 (3H, m),3.07-3.13 (1H, m), 3.82-3.86 (1H, m), 3.86 (3H, s), 5.08-5.13 (1H, m),6.10 (1H, d, J=2.0 Hz), 7.33 (1H, d, J=2.0 Hz), 7.38 (2H, t, J=7.8 Hz),7.51 (1H, tt, J=1.5, 7.3 Hz), 7.82-7.84 (2H, m).

(162e)(1S*,2R*,4S*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

To a solution of the(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate(293 mg, 0.976 mmol) prepared in Example 162d and 2,6-lutidine (0.136mL, 1.17 mmol) in dichloromethane (5.0 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.269 mL, 1.17 mmol) was added, and themixture was stirred at room temperature for 1 hour. To the reactionsolution, water (10 mL) was added, followed by extraction withdichloromethane (50 mL). The thus obtained organic layer was dried overanhydrous sodium sulfate. After vacuum concentration, the residue waspurified with silica gel chromatography (hexane/ethyl acetate=4:1) toyield the title compound (367 mg, 91%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.08 (3H, s), 0.09 (3H, s), 0.90 (9H, s),1.60-1.76 (3H, m), 2.00-2.05 (1H, m), 2.10-2.15 (1H, m), 2.24-2.28 (1H,m), 3.06-3.11 (1H, m), 3.76-3.83 (1H, m), 3.87 (3H, s), 5.09 (1H, dt,J=4.4, 10.3 Hz), 6.11 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=2.0 Hz), 7.38(2H, t, J=7.3 Hz), 7.51 (1H, tt, J=2.4, 8.8 Hz), 7.82-7.84 (2H, m).

(162f)(1S*,2R*,4S*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

A solution of the(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate (367 mg, 0.885 mmol) prepared in Example 162e and potassiumcarbonate (245 mg, 1.77 mmol) in methanol (5.0 mL) was stirred at roomtemperature for 3 hours. To the reaction solution, water (50 mL) wasadded, followed by extraction with ethyl acetate (50 mL). The thusobtained organic layer was washed twice with water (100 mL) and driedover anhydrous sodium sulfate. After vacuum concentration, the residuewas purified with silica gel chromatography (hexane/ethyl acetate=3:2)to yield the title compound (187 mg, 68%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.06 (3H, s), 0.07 (3H, s), 0.88 (9H, s),1.50-1.61 (3H, m), 1.96-2.06 (3H, m), 2.65-2.71 (1H, m), 3.57-3.62 (1H,m), 3.69-3.76 (1H, m), 3.83 (3H, s), 6.07 (1H, d, J=1.7 Hz), 7.37 (1H,s).

(162g)4-{[(1S*,2R*,4S*)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(152 mg, 0.333 mmol) prepared in Example 20a, the(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(94.0 mg, 0.303 mmol) prepared in Example 162f, sodium hydride (63%;17.3 mg, 0.454 mmol) and DMF (2.0 mL), to yield the title compound (81.5mg, 36%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H, s),1.50-1.82 (3H, m), 2.01-2.18 (3H, m), 3.15-3.20 (1H, m), 3.76 (6H, s),3.79-3.84 (1H, m), 3.93 (3H, s), 4.10-4.16 (1H, m), 5.19 (1H, d, J=16.6Hz), 5.23 (1H, d, J=16.6 Hz), 6.08 (1H, d, J=2.0 Hz), 6.38-6.40 (3H, m),7.17-7.21 (2H, m), 7.36 (1H, d, J=1.5 Hz), 7.93 (1H, d, J=7.3 Hz), 8.46(1H, d, J=5.9 Hz), 8.79 (1H, s).

(162h)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the 4-{[(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(81.5 mg, 0.109 mmol) prepared in Example 162g, tetrabutyl ammoniumfluoride (1.0 M solution in THF; 0.218 mL, 0.218 mmol) and THF (5.0 mL),to yield the title compound (66.5 mg, 89%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.49-1.79 (3H, m), 2.14-2.28 (3H, m),3.16-3.21 (1H, m), 3.76 (6H, s), 3.86-3.92 (1H, m), 3.92 (3H, s),4.11-4.18 (1H, m), 5.20 (2H, s), 6.07 (1H, d, J=2.0 Hz), 6.39-6.42 (3H,m), 7.17-7.21 (2H, m), 7.36 (1H, d, J=2.0 Hz), 7.94 (1H, d, J=7.3 Hz),8.46 (1H, d, J=5.9 Hz), 8.79 (1H, d, J=1.0 Hz).

(162i)5-Chloro-2-fluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(66.5 mg, 0.0975 mmol) prepared in Example 162h, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (39.2 mg, 83%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.56-1.77 (3H, m), 2.06-2.22 (3H, m),3.79-3.85 (1H, m), 3.88 (3H, s), 4.50-4.55 (1H, m), 4.81-4.89 (1H, m),6.18 (1H, d, J=2.0 Hz), 6.95-7.00 (2H, m), 7.26 (1H, d, J=2.0 Hz), 7.90(1H, d, J=7.3 Hz), 8.25 (1H, d, J=5.9 Hz), 8.52 (1H, s).

MS (ESI) m/z: 482 [M+H]+.

Example 1635-Chloro-2-fluoro-4-{[(1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(163a)(1S*,2R*,5R*)-5-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107a by using the(1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(774 mg, 2.49 mmol) prepared in Example 160a, triethylamine (2.08 mL,14.9 mmol), benzoyl chloride (1.45 mL, 12.6 mmol) and dichloromethane(8.0 mL), to yield the title compound (739 mg, 72%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.09 (3H, s), 0.14 (3H, s), 0.96 (9H, s),1.58-1.68 (2H, m), 1.79-1.85 (2H, m), 2.07-2.15 (1H, m), 2.29-2.33 (1H,m), 2.97-3.02 (1H, m), 3.88 (3H, s), 4.27-4.30 (1H, m), 5.56 (1H, dt,J=3.9, 10.3 Hz), 6.12 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=2.0 Hz), 7.37(2H, t, J=7.3 Hz), 7.50 (1H, tt, J=1.5, 7.3 Hz), 7.84-7.86 (2H, m).

(163b) (1S*,2R*,5R*)-5-Hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the(1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate (739 mg, 1.78 mmol) prepared in Example 163a, tetrabutylammonium fluoride (1.0 M solution in THF; 5.34 mL, 5.34 mmol) and THF(5.0 mL), to yield the title compound (517 mg, 97%) as a colorlesssolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.67-1.80 (2H, m), 1.87-1.96 (2H, m),2.08-2.16 (1H, m), 2.35-2.39 (1H, m), 3.04 (1H, dt, J=2.9, 10.3 Hz),3.90 (3H, s), 4.35 (1H, brs), 5.55 (1H, dt, J=3.9, 10.3 Hz), 6.15 (1H,d, J=2.0 Hz), 7.34-7.39 (3H, m), 7.51 (1H, t, J=7.3 Hz), 7.86 (2H, d,J=8.3 Hz).

(163c) (1S*,2R*)-2-(1-Methyl-1H-pyrazol-5-yl)-5-oxocyclohexyl benzoate

The reaction and aftertreatment were conducted in the same manner as inExample 107c by using the(1S*,2R*,5R*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate(517 mg, 1.72 mmol) prepared in Example 163b, a Dess-Martin reagent(1.46 g, 3.44 mmol) and dichloromethane (10 mL), to yield the titlecompound (441 mg, 86%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.97-2.06 (1H, m), 2.31-2.37 (1H, m),2.52-2.59 (1H, m), 2.62-2.69 (2H, m), 3.02-3.06 (1H, m), 3.46 (1H, dt,J=4.4, 9.3 Hz), 3.98 (3H, s), 5.47 (1H, dt, J=5.4, 8.8 Hz), 6.19 (1H, d,J=2.0 Hz), 7.40-7.43 (3H, m), 7.56 (1H, t, J=7.3 Hz), 7.88-7.90 (2H, m).

(163d) (1S*,2R*,5S*)-5-Hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 162d by using the(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)-5-oxocyclohexyl benzoate (441 mg,1.48 mmol) prepared in Example 163c, sodium borohydride (168 mg, 4.44mmol) and ethanol (7.0 mL), to yield the title compound (290 mg, 65%) asa colorless amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.44-1.65 (3H, m), 2.02-2.06 (1H, m),2.12-2.14 (1H, m), 2.55-2.59 (1H, m), 2.96 (1H, dt, J=3.9, 11.7 Hz),3.69-3.73 (1H, m), 3.87 (3H, s), 3.90-3.95 (1H, m), 5.16 (1H, dt, J=4.4,11.2 Hz), 6.05 (1H, d, J=2.0 Hz), 7.33 (1H, d, J=2.0 Hz), 7.38 (2H, t,J=7.8 Hz), 7.52 (1H, t, J=7.3 Hz), 7.83-7.85 (2H, m).

(163e)(1S*,2R*,5S*)-5-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate

The reaction and aftertreatment were conducted in the same manner as inExample 162e by using the(1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate(290 mg, 0.966 mmol) prepared in Example 163d, 2,6-lutidine (0.136 mL,1.17 mmol), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.269mL, 1.17 mmol) and dichloromethane (5.0 mL), to yield the title compound(327 mg, 82%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.09 (3H, s), 0.10 (3H, s), 0.89 (9H, s),1.45-1.67 (3H, m), 1.98-2.04 (2H, m), 2.43-2.47 (1H, m), 2.91-2.96 (1H,m), 3.84-3.89 (1H, m), 3.86 (3H, s), 5.16 (1H, dt, J=4.4, 11.2 Hz), 6.05(1H, d, J=2.0 Hz), 7.33 (1H, d, J=2.0 Hz), 7.37 (2H, t, J=7.3 Hz), 7.51(1H, tt, J=1.5, 7.3 Hz), 7.84-7.86 (2H, m).

(163f)(1S*,2R*,5S*)-5-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 162f by using the(1S*,2R*,5S*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexylbenzoate (327 mg, 1.09 mmol) prepared in Example 163e, potassiumcarbonate (301 mg, 2.18 mmol) and methanol (5.0 mL), to yield the titlecompound (207 mg, 87%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.08 (3H, s), 0.08 (3H, s), 0.89 (9H, s),1.34-1.45 (2H, m), 1.50-1.57 (1H, m), 1.86-1.94 (2H, m), 2.23-2.26 (1H,m), 2.55-2.59 (1H, m), 3.58-3.63 (1H, m), 3.72-3.78 (1H, m), 3.80 (3H,s), 6.00 (1H, s), 7.33 (1H, s).

(163g)4-{[(1S*,2R*,5S*)-5-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(152 mg, 0.333 mmol) prepared in Example 20a, the(1S*,2R*,5S*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(94.0 mg, 0.303 mmol) prepared in Example 163f, sodium hydride (63%;17.3 mg, 0.454 mmol) and DMF (2.0 mL), to yield the title compound (174mg, 77%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s),1.47-1.72 (3H, m), 2.01-2.05 (2H, m), 2.32-2.36 (1H, m), 2.98-3.03 (1H,m), 3.76 (6H, s), 3.78-3.82 (1H, m), 3.91 (3H, s), 4.16 (1H, dt, J=3.9,10.7 Hz), 5.19 (1H, d, J=16.6 Hz), 5.24 (1H, d, J=16.6 Hz), 6.00 (1H, d,J=2.0 Hz), 6.37-6.40 (3H, m), 7.18 (1H, d, J=8.8 Hz), 7.22 (1H, dd,J=1.0, 5.9 Hz), 7.34 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=7.3 Hz), 8.46(1H, d, J=6.4 Hz), 8.80 (1H, d, J=1.0 Hz).

(163h)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the4-{[(1S*,2R*,5S*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(174 mg, 0.233 mmol) prepared in Example 163g, tetrabutyl ammoniumfluoride (1.0 M solution in THF; 0.466 mL, 0.466 mmol) and THF (5.0 mL),to yield the title compound (148 mg, 93%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.46-1.69 (3H, m), 2.04-2.08 (1H, m),2.14-2.17 (1H, m), 2.46-2.49 (1H, m), 3.01-3.06 (1H, m), 3.76 (6H, s),3.81-3.88 (1H, m), 3.93 (3H, s), 4.18 (1H, dt, J=4.4, 10.7 Hz), 5.20(1H, d, J=17.1 Hz), 5.23 (1H, d, J=16.6 Hz), 6.01 (1H, d, J=2.0 Hz),6.39-6.43 (3H, m), 7.17 (1H, d, J=8.8 Hz), 7.22 (1H, d, J=5.9 Hz), 7.35(1H, d, J=2.0 Hz), 7.93 (1H, d, J=7.3 Hz), 8.46 (1H, d, J=6.4 Hz), 8.79(1H, s).

(163i)5-Chloro-2-fluoro-4-{[(1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(148 mg, 0.217 mmol) prepared in Example 163h, triethylsilane (0.10 mL),trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield thetitle compound (80.5 mg, 77%) as a colorless solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.45-1.75 (3H, m), 1.97-2.08 (2H, m),2.43-2.46 (1H, m), 3.10-3.15 (1H, m), 3.81-3.86 (1H, m), 3.88 (3H, s),4.56 (1H, dt, J=3.9, 10.7 Hz), 6.13 (1H, s), 6.96-7.01 (2H, m), 7.25(1H, s), 7.91 (1H, d, J=7.3 Hz), 8.25 (1H, d, J=6.4 Hz), 8.53 (1H, s).

MS (ESI) m/z: 482 [M+H]+.

Example 1645-Chloro-2-fluoro-4-{[(1R,2S,4S)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(164a)(1R,2S,4S)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanolprepared in Example 161a was optically resolved with CHIRALFLASH IC(Daicel Corp.; hexane/isopropanol=6:4) to yield the title compound as acolorless oil.

(164b)4-{[(1R,2S,4S)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(243 mg, 0.533 mmol) prepared in Example 20a, the(1R,2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(138 mg, 0.444 mmol) prepared in Example 164a, sodium hydride (63%; 25.4mg, 0.667 mmol) and DMF (2.0 mL), to yield the title compound (272 mg,82%) as a colorless oil.

(164c)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S,4S)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the4-{[(1R,2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(272 mg, 0.364 mmol) prepared in Example 164b, tetrabutyl ammoniumfluoride (1.0 M solution in THF; 0.729 mL, 0.729 mmol) and THF (5.0 mL),to yield the title compound (189 mg, 82%) as a colorless amorphoussolid.

(164d)5-Chloro-2-fluoro-4-{[(1R,2S,4S)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S,4S)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(189 mg, 0.299 mmol) prepared in Example 164c, triethylsilane (0.050mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), toyield the title compound (86.0 mg, 60%) as a colorless solid.

[α]_(D) ²⁵=−10.0 (c 1.04, DMSO).

Example 1655-Chloro-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(165a)(1S,2R,4R)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol

The(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanolprepared in Example 161a was optically resolved with CHIRALFLASH IC(Daicel Corp.; hexane/isopropanol=6:4) to yield the title compound as acolorless oil.

(165b)4-{[(1S,2R,4R)-4-{[Tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(238 mg, 0.522 mmol) prepared in Example 20a, the(1S,2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol(135 mg, 0.434 mmol) prepared in Example 165a, sodium hydride (63%; 24.8mg, 0.651 mmol) and DMF (2.0 mL), to yield the title compound (262 mg,81%) as a colorless oil.

(165c)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 120c by using the4-{[(1S,2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide(262 mg, 0.351 mmol) prepared in Example 165b, tetrabutyl ammoniumfluoride (1.0 M solution in THF; 0.702 mL, 0.702 mmol) and THF (5.0 mL),to yield the title compound (153 mg, 69%) as a colorless amorphoussolid.

(165d)5-Chloro-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(153 mg, 0.242 mmol) prepared in Example 165c, triethylsilane (0.050mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), toyield the title compound (92.0 mg, 79%) as a colorless solid.

[α]_(D) ²⁵=9.62 (c 0.915, DMSO).

Example 166(1R,3R,4S)-4-[2-Chloro-5-fluoro-4-(pyrimidin-4-ylsulfamoyl)phenoxy]-3-(1-methyl-1H-pyrazol-5-yl)cyclohexylacetate

A solution of the5-chloro-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(22.0 mg, 0.046 mmol) prepared in Example 165d, acetic anhydride (0.50mL) and 4-(N,N-dimethylamino)pyridine (0.6 mg, 0.0046 mmol) in pyridine(1.0 mL) was stirred at room temperature for 3 hours. The reactionsolution was concentrated, and 1 M HCl (10 mL) was then added to theresidue, followed by extraction with dichloromethane (50 mL). The thusobtained organic layer was dried over anhydrous sodium sulfate. Aftervacuum concentration, the residue was purified with silica gelchromatography (dichloromethane/methanol=10:1) to yield the titlecompound (22.0 mg, 91%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.68-1.75 (1H, m), 1.88-1.97 (2H, m),2.05-2.15 (2H, m), 2.15 (3H, s), 2.22-2.27 (1H, m), 3.40-3.45 (1H, m),3.94 (3H, s), 4.19 (1H, dt, J=3.9, 10.3 Hz), 5.18-5.19 (1H, m), 6.04(1H, d, J=2.0 Hz), 6.45 (1H, d, J=11.2 Hz), 7.26-7.27 (1H, m), 7.35 (1H,d, J=2.0 Hz), 7.96 (1H, d, J=7.3 Hz), 8.39 (1H, d, J=6.4 Hz), 8.82 (1H,s).

MS (ESI) m/z: 524 [M+H]+.

Example 1675-Chloro-2-fluoro-4-{[(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(167a)(3aS,7aS)-3a-(1-Methyl-1H-pyrazol-5-yl)hexahydro-1,3-benzodioxol-2-one

A solution of the(1S,2S)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (1.21 g, 6.17mmol) prepared in Example 123c, dimethylaminopyridine (75.3 mg, 0.62mmol) and carbonyldiimidazole (2.0 g, 12.3 mmol) in toluene (20 mL) wasstirred for 3 hours under heated reflux. To the reaction solution,carbonyldiimidazole (1.0 g, 6.17 mmol) was added, and the reactionsolution was further stirred for 3 hours under heated reflux. To thereaction solution, carbonyldiimidazole (0.50 g, 3.08 mmol) was furtheradded, and the reaction solution was stirred for 3 hours under heatedreflux. After allowing to cool, the reaction solution was vacuumconcentrated, and the residue was purified with silica gelchromatography (hexane/ethyl acetate=7:3) to yield the title compound(1.18 g, 86%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.26-1.35 (1H, m), 1.60-1.77 (3H, m),1.87-1.94 (1H, m), 2.02-2.08 (1H, m), 2.28-2.33 (2H, m), 4.02 (3H, s),4.90 (1H, t, J=3.4 Hz), 6.19 (1H, d, J=2.0 Hz), 7.45 (1H, d, J=2.0 Hz).

(167b) (1S,2S)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

A solution of the(3aS,7aS)-3a-(1-methyl-1H-pyrazol-5-yl)hexahydro-1,3-benzodioxol-2-one(500 mg, 2.25 mmol) prepared in Example 167a and palladium carbon (10%;500 mg) in THF (10 mL) was stirred at 60° C. for 12 hours under ahydrogen atmosphere. The reaction solution was filtered through celite,and the residue was purified with silica gel chromatography(hexane/ethyl acetate=2:1) to yield the title compound (85 mg, 21%) as acolorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.34-1.44 (2H, m), 1.50-2.00 (6H, m),2.83-2.87 (1H, m), 3.80 (3H, s), 3.94-3.96 (1H, m), 6.15 (1H, d, J=2.0Hz), 7.39 (1H, d, J=1.0 Hz).

(167c)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(98.0 mg, 0.215 mmol) prepared in Example 20a, the(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (38.7 mg, 0.215 mmol)prepared in Example 167b, sodium hydride (63%; 12.0 mg, 0.315 mmol) andDMF (1.0 mL), to yield the title compound (98.0 mg, 74%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.47-1.98 (6H, m), 2.13-2.28 (2H, m),2.97-3.00 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.85 (3H, s), 4.58-4.59(1H, m), 5.21 (1H, d, J=16.6 Hz), 5.25 (1H, d, J=16.6 Hz), 6.17 (1H, d,J=2.0 Hz), 6.39-6.41 (3H, m), 7.19 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=6.4Hz), 7.28 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=7.3 Hz), 8.47 (1H, d, J=5.9Hz), 8.80 (1H, s).

(167d)5-Chloro-2-fluoro-4-{[(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(98.0 mg, 0.159 mmol) prepared in Example 167c, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (67.0 mg, 90%) as a colorless solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.48-1.84 (6H, m), 1.99-2.10 (2H, m),3.18-3.21 (1H, m), 3.80 (3H, s), 4.91-4.92 (1H, m), 5.99 (1H, d, J=2.0Hz), 6.96 (1H, brs), 7.10-7.12 (2H, m), 7.83 (1H, d, J=7.3 Hz), 8.26(1H, brs), 8.58 (1H, s).

MS (ESI) m/z: 466 [M+H]+;

[α]_(D) ²⁵=120.8 (c 1.04, DMSO).

Example 1685-Chloro-2-fluoro-4-{[(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(168a) (1R,2R)-1-(1-Methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol

The reaction and aftertreatment were conducted in the same manner as inExample 102a by using the 5-(cyclohex-1-en-1-yl)-1-methyl-1H-pyrazole(1.00 g, 6.16 mmol) prepared in Example 123b, methanesulfonamide (586mg, 6.16 mmol), t-butanol (10 mL), water (10 mL) and AD-mixβ(Sigma-Aldrich Corp.; 8.67 g), to yield the title compound (1.21 g, 99%)as a colorless oil.

(168b)(3aR,7aR)-3a-(1-Methyl-1H-pyrazol-5-yl)hexahydro-1,3-benzodioxol-2-one

The reaction and aftertreatment were conducted in the same manner as inExample 167a by using the(1R,2R)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (1.21 g, 6.17mmol) prepared in Example 168a, dimethylaminopyridine (75.3 mg, 0.62mmol), carbonyldiimidazole (3.50 g, 21.6 mmol) and toluene (20 mL), toyield the title compound (1.26 g, 92%) as a colorless oil.

(168c) (1R,2R)-2-(1-Methyl-1H-pyrazol-5-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 167b by using the(3aR,7aR)-3a-(1-methyl-1H-pyrazol-5-yl)hexahydro-1,3-benzodioxol-2-one(760 mg, 3.42 mmol) prepared in Example 168b, palladium carbon (10%; 760mg) and THF (10 mL), to yield the title compound (133 mg, 22%) as acolorless oil.

(168d)5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using the5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide(80.0 mg, 0.175 mmol) prepared in Example 20a, the(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (31.6 mg, 0.175 mmol)prepared in Example 168c, sodium hydride (63%; 8.0 mg, 0.210 mmol) andDMF (1.0 mL), to yield the title compound (55.0 mg, 51%) as a colorlessoil.

(168e)5-Chloro-2-fluoro-4-{[(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1b by using the5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide(55.0 mg, 0.0893 mmol) prepared in Example 168d, triethylsilane (0.10mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), toyield the title compound (41.6 mg, 99%) as a colorless solid.

MS (ESI) m/z: 466 [M+H]+;

[α]_(D) ²⁵=−116.1 (c 1.01, DMSO).

Example 1692,6-Difluoro-4-{[(1R,2S)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(169a) (1R*,2S*)-2-(1H-Pyrazol-4-yl)cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 155b by using 4-iodo-1H-pyrazole (5.82 g, 30.0 mmol), butyllithium (2.69 M solution in hexane; 22.3 mL, 60.0 mmol), a borontrifluoride-diethyl ether complex (7.54 mL, 60.0 mmol), cyclohexeneoxide (3.24 g, 33.0 mmol) and THF (120 mL), to yield the title compound(0.48 g, 10%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.26-1.51 (4H, m), 1.73-2.11 (4H, m),2.43-2.48 (1H, m), 3.41-3.46 (1H, m), 7.51 (2H, s).

(169b) (1R,2S)-2-(1H-Pyrazol-4-yl)cyclohexanol

The (1R*,2S*)-2-(1H-pyrazol-4-yl)cyclohexanol prepared in Example 169awas optically resolved with CHIRALPAK AD-H (Daicel Corp.;hexane/ethanol=8:2) to yield the title compound as a colorless solid.

(169c) (1R,2S)-2-[1-(Methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol

To a solution of the (1R,2S)-2-(1H-pyrazol-4-yl)cyclohexanol (170 mg,1.02 mmol) prepared in Example 169b in DMF (5.0 mL), chloromethyl methylether (0.078 mL, 1.02 mmol) was added, and the reaction solution wasstirred at room temperature for 2 hours. The reaction solution wasvacuum concentrated, and the residue was then purified with silica gelchromatography (hexane/ethyl acetate=7:3) to yield the title compound(132 mg, 61%) as a colorless solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.26-1.48 (4H, m), 1.74-2.09 (4H, m),2.39-2.44 (1H, m), 3.34 (3H, s), 3.40-3.44 (1H, m), 5.35 (2H, s), 7.46(1H, s), 7.49 (1H, s).

(169d)N-(2,4-Dimethoxybenzyl)-2,6-difluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(178 mg, 0.405 mmol) prepared in Example 27a, the(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol (71.0 mg,0.338 mmol) prepared in Example 169c, sodium hydride (63%; 19.3 mg,0.507 mmol) and DMF (2.0 mL), to yield the title compound (62.2 mg, 29%)as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.37-1.65 (4H, m), 1.81-2.19 (4H, m),2.78-2.84 (1H, m), 3.22 (3H, s), 3.77 (3H, s), 3.82 (3H, s), 3.98-4.04(1H, m), 5.26 (2H, s), 5.28 (2H, s), 6.35-6.44 (4H, m), 7.18 (1H, dd,J=1.2, 5.9 Hz), 7.21 (1H, d, J=8.2 Hz), 7.34 (1H, s), 7.41 (1H, s), 8.44(1H, d, J=6.3 Hz), 8.78 (1H, d, J=0.8 Hz).

(169e)2,6-Difluoro-4-{[(1R,2S)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 147e by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(62.2 mg, 0.0988 mmol) prepared in Example 169d, triethylsilane (0.080mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol(6.0 mL) and 6 M hydrochloric acid (2.0 mL), to yield the title compound(37.0 mg, 85%) as a colorless solid.

[α]_(D) ²⁵=−23.0 (c 1.04, DMSO).

Example 1702-Fluoro-5-methyl-4-{[(1R,2S)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(170a)N-(2,4-Dimethoxybenzyl)-2-fluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(154 mg, 0.354 mmol) prepared in Example 43a, the(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol (61.8 mg,0.294 mmol) prepared in Example 169c, sodium hydride (63%; 16.8 mg,0.441 mmol) and DMF (2.0 mL), to yield the title compound (144 mg, 78%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41-1.65 (4H, m), 1.80-2.20 (4H, m),2.14 (3H, s), 2.85-2.90 (1H, m), 3.20 (3H, s), 3.76 (3H, s), 3.79 (3H,s), 4.00-4.04 (1H, m), 5.25 (2H, s), 5.27 (2H, s), 6.38-6.41 (3H, m),7.19 (1H, d, J=8.3 Hz), 7.30 (1H, dd, J=1.5, 5.9 Hz), 7.34 (1H, s), 7.41(1H, s), 7.68 (1H, d, J=7.8 Hz), 8.42 (1H, d, J=5.9 Hz), 8.76 (1H, d,J=1.0 Hz).

(170b)2-Fluoro-5-methyl-4-{[(1R,2S)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 147e by using theN-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(144 mg, 0.230 mmol) prepared in Example 170a, triethylsilane (0.184mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol(15 mL) and 6 M hydrochloric acid (5.0 mL), to yield the title compound(51.7 mg, 52%) as a colorless solid.

[α]_(D) ²⁵=−20.3 (c 0.979, DMSO).

Example 1712,6-Difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(171a) (1S,2R)-2-(1H-Pyrazol-4-yl)cyclohexanol

The (1R*,2S*)-2-(1H-pyrazol-4-yl)cyclohexanol prepared in Example 169awas optically resolved with CHIRALPAK AD-H (Daicel Corp.;hexane/ethanol=8:2) to yield the title compound as a colorless solid.

(171b) (1S,2R)-2-[1-(Methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol

The reaction and aftertreatment were conducted in the same manner as inExample 169c by using the (1S,2R)-2-(1H-pyrazol-4-yl)cyclohexanol (144mg, 0.866 mmol) prepared in Example 171a, chloromethyl methyl ether(0.069 mL, 0.908 mmol) and DMF (4.0 mL), to yield the title compound(132.2 mg, 73%) as a colorless oil.

(171c)N-(2,4-Dimethoxybenzyl)-2,6-difluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide(156 mg, 0.355 mmol) prepared in Example 27a, the(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol (62.2 mg,0.296 mmol) prepared in Example 171b, sodium hydride (63%; 16.9 mg,0.444 mmol) and DMF (2.0 mL), to yield the title compound (40.5 mg, 22%)as a colorless oil.

(171d)2,6-Difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 147e by using theN-(2,4-dimethoxybenzyl)-2,6-difluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide(40.5 mg, 0.0643 mmol) prepared in Example 171c, triethylsilane (0.055mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol(6.0 mL) and 6 M hydrochloric acid (2.0 mL), to yield the title compound(28.0 mg, 99%) as a colorless solid.

Example 1722-Fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

(172a)N-(2,4-Dimethoxybenzyl)-2-fluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 1a by using theN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(174 mg, 0.400 mmol) prepared in Example 43a, the(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol (70.0 mg,0.333 mmol) prepared in Example 171a, sodium hydride (63%; 19.0 mg,0.499 mmol) and DMF (2.0 mL), to yield the title compound (61.5 mg, 30%)as a colorless oil.

(172b)2-Fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide

The reaction and aftertreatment were conducted in the same manner as inExample 147e by using theN-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide(61.5 mg, 0.0983 mmol) prepared in Example 172a, triethylsilane (0.079mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol(15 mL) and 6 M hydrochloric acid (5.0 mL), to yield the title compound(42.0 mg, 99%) as a colorless solid.

[α]_(D) ²⁵=16.1 (c 0.943, DMSO).

Preparation Example 1

Tablets can be obtained by mixing 5 g of the compound of Example 119, 90g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate with a blender and subjecting the thus obtainedmixture to tablet compression by using a tableting machine.

Preparation Example 2

Tablets can be obtained by mixing 5 g of the compound of Example 122, 90g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate with a blender and subjecting the thus obtainedmixture to tablet compression by using a tableting machine.

Preparation Example 3

Tablets can be obtained by mixing 5 g of the compound of Example 124, 90g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate with a blender and subjecting the thus obtainedmixture to tablet compression by using a tableting machine.

Preparation Example 4

Tablets can be obtained by mixing 5 g of the compound of Example 143, 90g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate with a blender and subjecting the thus obtainedmixture to tablet compression by using a tableting machine.

Preparation Example 5

Tablets can be obtained by mixing 5 g of the compound of Example 171, 90g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate with a blender and subjecting the thus obtainedmixture to tablet compression by using a tableting machine.

Test Example 1 Construction and Cultivation of Cell Lines

HNav 1.7 and hNav β1 and β2 subunits cloned from human brain were stablyexpressed by using Lipofectamine (Invitrogen Corp.) in HEK293A cells,and stably expressing cell lines of hNav 1.7/β1/β2 were selected bytaking an amount of expression as an indicator. As the culture medium,DMEM (Invitrogen Corp.) containing 20% fetal bovine serum (HycloneLaboratories, Inc.), 100 U/ml penicillin (Invitrogen Corp.), 100 μg/mlstreptomycin (Invitrogen Corp.), 200 μg/ml hygromycin B (InvitrogenCorp.), 200 μg/ml Zeocin (Invitrogen Corp.) and 1 puromycin (ClontechLaboratories, Inc.) was used.

Test Example 2 Electrophysiological Evaluation (J. Biomol. Screen., 2006August; 11(5): 488-96.)

Current record was obtained by an automated patch clamp system “IonWorksQuattro (Molecular Devices Corporation)” in Population Patch Clamp mode.The operation was conducted in accordance with the operating procedureof the system. A Dulbecco's phosphate buffer containing calcium andmagnesium (Sigma) was used as an extracellular fluid, and a lowCl-buffer (100 mM K-gluconate, 40 mM KCl, 3.2 mM MgCl₂, 5 mM EGTA, 5 mMHepes, pH 7.3) was used as an intracellular fluid. A test compound wasdissolved in dimethylsulfoxide (DMSO) to prepare a 30 mM stock solution,so as to produce 4-fold serial dilutions with the extracellular fluidfor attaining a DMSO concentration of 0.3% in measurement.

The hNav 1.7/β1/β2 cells cultured to a 70-80% confluent state in a T150flask (Sumilon) were washed with PBS and subsequently with versene(Invitrogen Corp.), and collected by allowing to react with 0.05%trypsin (Invitrogen Corp.) at 37° C. for 3 minutes. After washing with aculture medium, the resultant cells were suspended in an extracellularfluid at a concentration of 2×10⁻⁶ cells/ml so as to be used for themeasurement. The cell membrane was perforated by using an intracellularfluid including 100 μg/ml amphotericin B (Sigma).

Current response was obtained at a sampling frequency of 10 kHz. Leakagecurrent correction was performed by applying a step pulse of −110 mVbefore a test pulse. The membrane potential was fixed at −100 mV for 5seconds immediately before applying the test pulse.

In order to check the state-dependency of the inhibiting activity of atest compound, the test pulse was

applied as follows: After applying a depolarization pulse of −10 mV for5 msec., the potential was fixed at −100 mV for 200 msec., a potential(V½) at which approximately 50% of channels are inactivated was held for2 seconds, and a depolarization pulse of −10 mV was applied for 50 msec.Such a test pulse was applied before adding the test compound and aftercultivation of 5 minutes and 30 seconds with a solution of the testcompound gradually added by 3.5 μl at each time. Since IonWorks Quattrohas a measuring electrode head (E-head) and an agent supplying head(F-head) separated from each other, the membrane potential was notclamped during the addition and the cultivation of the test compound.

The inhibiting activity of the test compound was analyzed with respectto the responses to the two depolarization pulses. Data to be analyzedwas selected under conditions that a ratio of a resistance valueattained before adding the test compound to a resistance value attainedafter the addition fell in a range of 0.5 to 1.6, that a seal resistancevalue was 30 MΩ or more, and that the current response obtained beforeadding the test compound was ⅓ or more of an average of all wells. Aninhibiting activity value was determined on the basis of currentsgenerated in response to the depolarization pulses applied before andafter adding the test compound, and a 50% inhibition concentration(IC₅₀) was calculated by regression analyzing a 6-point concentrationresponse curve in accordance with the following sigmoidal dose-responsefunction:

y=Bottom+(Top−Bottom)(1+10̂[(Log EC50−x)×Hill slope])

The values of IC₅₀ of the inhibiting activity of test compoundscorresponding to the response caused by the second depolarization pulse(with a pre-pulse potential set to V½) are shown in Tables 7-1 and 7-2.

TABLE 7-1 Compound hNav1.7 IC₅₀ (Example No.) (μM) 1 0.12 2 0.020 3 0.274 0.012 5 0.29 6 0.61 7 0.45 8 0.017 9 0.014 10 0.030 11 0.010 12 0.1213 0.082 14 0.15 15 0.028 16 0.23 17 0.51 18 0.17 19 0.51 20 0.045 210.25 22 0.52 23 0.13 24 0.023 25 0.095 26 0.20 27 0.043 28 0.046 29 1.830 0.50 31 0.058 32 1.0 33 0.30 34 0.25 35 0.099 36 0.50 37 0.21 38 0.2439 1.0 40 0.33 41 0.16 42 0.091 43 0.024 44 0.33 45 0.19 46 0.030 470.12 48 0.016 49 0.66 50 0.047 51 0.75 52 0.083 53 0.33 54 0.039 550.039 56 0.25 57 0.075 58 0.66 59 0.031 60 0.037 61 0.0026 62 0.12 630.028 64 0.031 65 0.13 66 0.017 67 0.043 68 0.086 69 0.087 70 0.33 710.15 72 0.036 73 0.10 74 — 75 >10 76 — 77 — 78 43 79 0.070 80 0.086 810.15 82 0.056 83 0.65 84 0.036 85 0.17 86 0.036

TABLE 7-2 Compound hNav1.7 IC₅₀ (Example No.) (μM) 87 0.28 88 0.32 890.13 90 0.089 91 0.17 92 1.0 93 0.065 94 0.12 95 0.17 96 0.25 97 0.03498 0.046 99 0.41 100 0.38 101 0.18 102 0.036 103 0.32 104 0.071 105 0.22106 0.27 107 0.042 108 1.7 109 0.050 110 0.30 111 0.030 112 0.31 113 1.0114 0.078 115 0.58 116 0.17 117 0.75 118 21 119 0.10 120 0.27 121 0.93122 0.020 123 — 124 2.4 125 0.20 126 0.014 127 0.12 128 92 129 0.10 1300.88 131 0.059 132 0.20 133 0.057 134 0.034 135 0.051 136 0.29 137 0.030138 0.024 139 0.035 140 0.034 141 0.058 142 47 143 0.021 144 3.4 145 —146 0.024 147 0.60 148 0.018 149 32 150 0.021 151 33 152 0.017 153 >100154 0.017 155 0.028 156 0.041 157 0.050 158 0.028 159 9.8 160 0.56 1610.13 162 0.82 163 0.19 164 >10 165 0.040 166 0.059 167 4.6 168 >10169 >10 170 >10 171 0.043 172 0.034

Test Example 3 Thermal Hyperalgesia Assay

In the present invention, mice and rats affected by thermal hyperalgesiawere used for evaluation.

A test compound was orally administered to an animal, and the thermalhyperalgesia was evaluated at each measurement time determined by astudy director. Specifically, thermal stimulation was applied to thesole of hind paw of the animal, and latency until it showed escapebehaviors such as licking and shaking was measured.

The test compound was evaluated by calculating a improvement rate ofpain score (%) at a constant dose against the vehicle treatment group.Improvement rates of pain score (%) at a constant dose are shown inTables 8-1 and 8-2 as “C” when the rate was 0 to 30%, as “B” when therate was 31 to 60%, and as “A” when the rate was 61 to 100%.

TABLE 8-1 Compound Ratio of improving (Example No.) pain score (%) 1 — 2— 3 — 4 — 5 — 6 — 7 — 8 — 9 — 10 — 11 — 12 — 13 — 14 — 15 A 16 — 17 — 18— 19 — 20 — 21 — 22 — 23 A 24 — 25 A 26 — 27 — 28 C 29 A 30 B 31 A 32 —33 A 34 — 35 B 36 — 37 C 38 A 39 — 40 A 41 B 42 C 43 B 44 C 45 C 46 C 47A 48 A 49 — 50 B 51 B 52 B 53 — 54 C 55 C 56 B 57 B 58 B 59 C 60 C 61 —62 B 63 C 64 C 65 B 66 A 67 C 68 B 69 B 70 — 71 A 72 C 73 A 74 — 75 — 76— 77 — 78 C 79 C 80 C 81 C 82 B 83 B 84 B 85 B 86 A

TABLE 8-2 Compound Ratio of improving (Example No.) pain score (%) 87 B88 C 89 — 90 B 91 A 92 — 93 B 94 A 95 C 96 A 97 C 98 C 99 — 100 — 101 B102 — 103 B 104 B 105 A 106 — 107 B 108 A 109 B 110 B 111 A 112 — 113 —114 B 115 A 116 B 117 — 118 A 119 A 120 C 121 — 122 A 123 — 124 — 125 C126 C 127 A 128 B 129 C 130 — 131 C 132 A 133 A 134 B 135 B 136 B 137 A138 B 139 C 140 B 141 A 142 C 143 B 144 — 145 — 146 C 147 C 148 B 149 —150 C 151 — 152 B 153 — 154 — 155 — 156 — 157 — 158 C 159 — 160 — 161 —162 — 163 — 164 — 165 B 166 — 167 — 168 — 169 — 170 — 171 B 172 —

INDUSTRIAL APPLICABILITY

The present compound or a pharmacologically acceptable salt thereof isuseful because it can be used as an active ingredient of apharmaceutical composition for treating and/or preventing pain, andsodium channel associated diseases or disorders such as central nervoussystem disorders.

1. A compound represented by formula (I):

or a pharmacologically acceptable salt thereof, wherein Ar¹ and Ar² areeach independently a heteroaryl group or an aryl group; R¹, R² and R³are each independently a hydrogen atom, a halogen atom, a C1-C6 alkylgroup, a halogenated C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, aC1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group or a cyanogroup; R⁴ and R⁵ are each independently a hydrogen atom, a halogen atom,a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl group,a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7cycloalkyl group or a C1-C6 alkoxy group; and n is an integer of 1 to 3;wherein the heteroaryl group or the aryl group is optionally substitutedwith one or two groups independently selected from a halogen atom, aC1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, ahydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7cycloalkyl group, a carboxy group, a cyano group, an amino group, aC1-C3 alkylamino group and a di-C1-C3 alkylamino group; and when theheteroaryl group or the aryl group is substituted with two such groups,the two groups are the same as or different from each other.
 2. Thecompound or a pharmacologically acceptable salt thereof according toclaim 1, wherein in formula (I), Ar¹ and Ar² are each independently aheteroaryl group; R¹, R² and R³ are each independently a hydrogen atom,a halogen atom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group ora C3-C7 cycloalkyl group; R⁴ and R⁵ are each independently a hydrogenatom, a halogen atom, a C1-C6 alkyl group or a halogenated C1-C6 alkylgroup; and the heteroaryl group is optionally substituted with one ortwo groups selected from the group consisting of a halogen atom, a C1-C6alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, ahydroxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, an amino group, aC1-C3 alkylamino group and a di-C1-C3 alkylamino group.
 3. The compoundor a pharmacologically acceptable salt thereof according to claim 1,wherein the heteroaryl group is a 5- or 6-membered nitrogen-containingaromatic heterocyclic group.
 4. The compound or a pharmacologicallyacceptable salt thereof according to claim 1, wherein Ar¹ is a pyridylgroup, a pyridazinyl group, a pyrimidinyl group, a pyrazolyl group or animidazolyl group, and wherein Ar¹ is optionally substituted.
 5. Thecompound or a pharmacologically acceptable salt thereof according toclaim 4, wherein Ar¹ is optionally substituted with one or two groupsselected from the group consisting of a chlorine atom, a fluorine atom,a methyl group, an ethyl group, a trifluoromethyl group, an amino group,a methylamino group and a dimethylamino group.
 6. The compound or apharmacologically acceptable salt thereof according to claim 1, whereinAr² is a thiadiazolyl group, a thiazolyl group, a pyrimidinyl group, anisoxazolyl group, an oxazolyl group or an isothiazolyl group, andwherein Ar² is optionally substituted.
 7. The compound or apharmacologically acceptable salt thereof according to claim 6, whereinAr² is optionally substituted with a chlorine atom, a fluorine atom or amethyl group.
 8. The compound or a pharmacologically acceptable saltthereof according to claim 1, wherein R¹, R² and R³ are eachindependently a hydrogen atom, a chlorine atom, a fluorine atom, amethyl group, an ethyl group, a trifluoromethyl group or a cyano group.9. The compound or a pharmacologically acceptable salt thereof accordingto claim 1, wherein R⁴ and R⁵ are each independently a hydrogen atom, afluoro group or a methyl group.
 10. The compound or a pharmacologicallyacceptable salt thereof according to claim 1, wherein the compoundrepresented by formula (I) is2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide;3-chloro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,5-difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,5-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-2-(3-amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-2-(3-amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-2-(3-amino-1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;2,6-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide;or2,6-difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide.11. The compound or a pharmacologically acceptable salt thereofaccording to claim 1, wherein the compound represented by formula (I) is2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,5-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,6-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-5-methyl-4-{[(1S,2R)-2-(1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;or2,6-difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide.12. The compound or a pharmacologically acceptable salt thereofaccording to claim 1, wherein the compound represented by formula (I) is2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2,6-difluoro-4-{[(1S*,2R*)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide;5-chloro-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;4-{[(1S,2R)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide;or2,6-difluoro-4-{[(1S,2R)-2-(1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide.13. A pharmaceutical composition comprising a compound or apharmacologically acceptable salt thereof according to claim 1, and apharmaceutically acceptable carrier. 14-27. (canceled)
 28. A method fortreating or preventing pain, comprising administering a compound or apharmacologically acceptable salt thereof according to claim 1 to amammal.
 29. A method for treating or preventing a disease or symptom,comprising administering a compound or a pharmacologically acceptablesalt thereof according to claim 1 to a mammal, wherein the disease orsymptom is selected from: acute pain; chronic pain; pain caused byinjury of soft tissues or peripheral tissues; postherpetic neuralgia;central pain; neuropathic pain; migraine; pain associated withosteoarthritis or rheumatoid arthritis; contusion; pain associated withsprain or trauma; spondylalgia; pain caused by injury of a spinal cordor a brain stem; low back pain; sciatic neuralgia; toothache; myofascialpain syndrome; perineal section pain; gout pain; cardiac pain; musclepain; eye pain; inflammatory pain; orofacial pain; abdominal pain;dysmenorrhea; labor pain or pain associated with endometriosis; somaticpain; pain associated with nerve or radicular injury; amputation; ticdouloureux; pain associated with neuroma or vasculitis; pain caused bydiabetic neuropathy or diabetic peripheral neuropathic pain; pain causedby chemotherapy-induced neuropathy; atypical prosopalgia; neuropathiclow back pain; trigeminal neuralgia; occipital neuralgia; myelomere orintercostal neuralgia; HIV-associated neuralgia; AIDS-associatedneuralgia; hyperalgesia; pain of thermal burn; idiopathic pain; paincaused by chemotherapy; occipital neuralgia; psychogenic pain; painassociated with gallstone; neuropathic or non-neuropathic painassociated with cancer; phantom limb pain; functional abdominal pain;headache; acute or chronic tension headache; sinus headache; clusterheadache; temporomandibular joint pain; maxillary sinus pain; paincaused by ankylosing spondylarthritis; postoperative pain; scar pain;chronic non-neuropathic pain; fibromyalgia; amyotrophic lateralsclerosis; epilepsy (including, partial epilepsy, adult epilepsy partialseizure and partial seizure of an epileptic patient); generalizedanxiety disorder; and restless legs syndrome.
 30. A method for treatingor preventing pain caused by diabetic neuropathy, comprisingadministering a compound or a pharmacologically acceptable salt thereofaccording to claim 1 to a mammal.
 31. A method for treating orpreventing a sodium channel associated disease, comprising administeringa compound or a pharmacologically acceptable salt thereof according toclaim 1 to a mammal.
 32. The method of claim 28, wherein the mammal is ahuman.
 33. The method of claim 29, wherein the mammal is a human. 34.The method of claim 30, wherein the mammal is a human.
 35. The method ofclaim 31, wherein the mammal is a human.